ISSN 1866-8836
Клеточная терапия и трансплантация
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Introduction

Stromal cells of the hematopoietic microenvironment are the progeny of mesenchymal stem cells (MSC). MSC are non-hematopoietic multipotent stem cells able to differentiate into different cells lines, such as osteoblasts, adipocytes, chondrocytes, fibroblasts, and other cell lines [1]. The ability to self-renew has not been proven for human MSC [2]; however, these cells are known to have high proliferative potential when cultured. Murine MSC are able to transfer a hematopoietic microenvironment in vivo at least 9 times, confirming their ability for self-maintenance [3]. Until now, the data about phenotypical markers of MSC has not been developed sufficiently [4], but MSC are able to express the number of non-specific markers [5]. It was shown recently that fibroblast activation protein perfectly identifies mesenchymal stromal cells [6]. The compartment of stromal precursor cells can be characterized by physiological methods according to the first 25 years of hematopoietic stem cells (HSC) research. Explantation of bone marrow cell suspension into culture flasks led to the development of discrete fibroblast-like colonies. Each colony represents a clone produced by single clonogenic precursor cells–colony-forming unit fibroblasts (CFU-F) [7]. CFU-F are of mesenchymal origin and do not develop from HSC [8, 9]. CFU-F are heterogenic cell populations and some of them possess high proliferative potential; their ability to differentiate could be associated with MSC [10]. The transplantation of the pull of colonies into the organism leads to the development of different tissues, including bone and adipose tissues [11, 12]. The comparison of CFU-F with MSC is questionable because CFU-F are able to differentiate inside the diffusion chambers after implantation to the organism, but it is not known whether they are able to transfer the full microenvironment or self-maintain. Recent data suggests that CD146+ CFU-F with high proliferative capacity, are able to transfer the microenvironment, but this can be applied only to rare cells in the bone marrow [13]. Moreover, human multipotent stromal cells readily form single-cell-derived colonies, which are heterogeneous because cells from a colony form new colonies that vary in size and differentiation potential [14]. Several growth factors influence the CFU-F growth, and four of them are necessary for CFU-F development: PDGF, bFGF, TGFβ and EGF [15]. The proliferative potential of CFU-F is not studied in detail, but it is known that most of the CFU-F in the organism are not cycling and remain in the “Go” phase [16]. However, CFU-F start to proliferate when transferred to cultures.

The compartments of MSC and HSC have hierarchical structures. This is well known for HSC, but in the case of MSC it was discovered for the first time in experiments with ectopic foci formation in vivo. At 6 weeks after implantation of the donor bone marrow plug under the renal capsule of the syngeneic recipient, ectopic hematopoietic foci developed at the site of transplantation. In such foci, stromal cells belong to the donor, and hematopoietic cells belong to the recipient. Multiple histological examinations during foci formation have revealed that the hematopoietic microenvironment was built de novo. The method of ectopic foci formation is not only qualitative, but also quantitative. The size of the hematopoietic territory is defined by the number of MSCs transplanted, and restricted accordingly to the number of niches transferred with the bone marrow plug; since the foci size is proportional to the amount of implanted bone marrow. It is possible to transfer the foci under the renal capsule of the secondary recipient. In this case foci again would be built de novo due to the presence of MSC. The foci sustain at least 9 re-transplantations that prove the high capability of MSC to self-renew [3]. The radio-sensitivity of MSC is much lower than that of HSC [17]. In summarizing this data it is possible to conclude that stromal precursor cells that are able to transfer the microenvironment are true stem cells and the method of ectopic foci formation allows the opportunity to estimate their numbers in bone marrow.

In irradiated recipients foci formed after the implantation of bone marrow plugs are enlarged 2-3 fold in comparison with foci developed in non-irradiated mice. However, the re-transplantation of these enlarged foci to non-irradiated recipients led to the formation of foci of normal size. Thus, in the enlarged foci the number of MSC do not increase, and the microenvironment created in the irradiated recipients is enlarged by cells other than MSC inducible precursor cells, which are not able to self-renew [18]. Such stromal multipotent precursor (SMP) cells have the position in the hierarchy of MSC similar to the position of the multipotent precursor in the hierarchy of HSC. The position of CFU-F in the hierarchy of MSC is unknown. It is possible to define it by studying the concentration of CFU-F in ectopic foci formed in non-irradiated and irradiated recipients. There are three possible variants for the irradiated recipients: the concentration of CFU-F could increase, decrease, or remain unchanged. We suppose that CFU-F could be considered to be the progeny of SMP in cases where their concentration in enlarged foci do not change and their numbers increase 2-3 fold according to the foci size. In cases of both decreased concentration and number of CFU-F in enlarged foci, it is possible to assume that these precursor cells with limited proliferative potential are used irreversibly to form SMP, thus CFU-F are located higher than SMP in the hierarchy of MSC and have the position directly before SMP. If the actual number of CFU-F in the enlarged foci do not change, one could conclude that there are precursors that do not take part in the formation of the microenvironment and represent special populations of stromal clonogenic cells.

The measurement of the concentration and number of CFU-F in ectopic foci in irradiated and non-irradiated recipients performed in this study defines the position of CFU-F immediately after MSC and before SMP in the hierarchy of mesenchymal stem cells.

Materials and methods

The hybrid mice (СВАхC57Bl/6) F1 at the age of 12-16 weeks at the beginning of the experiment were used. The animals were irradiated on the IPK 137Cs irradiator with a dose rate of 16 сGy/min.

For CFU-F analysis 106 bone marrow cells were seeded into the T25 flask in 5 ml αМЕМ (ICN) with 20% fetal bovine serum (Hyclone) and 5 ng/ml basic Fibroblast Growth Factor (bFGF) (donated by Gasparian M.E., Lab. of Protein engineering, IBC, RAS). Cells were cultivated for 14 days in 370С and 5% СО2. Formed colonies were stained with 0.1% crystal violet on 20% methanol and counted under the inverted microscope (the colony was counted if it contained no less than 50 cells).

For cloning of individual CFU-F, bone marrow cells were planted into a 96-well plate in concentrations from 30,000 to 50,000 of nucleated cells per well in standard media. In this cultivation system the most convenient concentration turned out to be 30,000 cells per well (Table 1). In this assay the frequency of CFU-F was calculated by means of the Poisson equation:

2008-2-en-Shipounova-et-al-MSC-Equation.jpg

Table 1. Frequency of CFU-F in the bone marrow of mice

2008-2-en-Shipounova-et-al-MSC-Table-1.jpg

Clones from the wells containing single colonies were transferred into 24-well plates, then into 6-well plates, and finally into T25 flasks. For each procedure, the cells were washed with Versen solution and detached with 0.25% tripsin solution. The proliferative potential of CFU-F was estimated by their ability to form a confluent monolayer during sequential transfers from small to large available growth areas. The number of divisions performed by CFU-F progeny was evaluated by the assumption that the number of cells in the confluent monolayer increases proportionally to the growth area. For instance, the bottom square of the well in a 96-well plate is 0.32 cm2; 24-well, 1.88 cm2; 6-well, 9.4 cm2; and a Т25 flask is 25 cm2. If the confluent monolayer is transferred from one well of a 96-well plate into one well of a 24-well plate, the size of available growth area increases 6-fold; from a 24-well plate to a 6-well plate is 5-fold; and from a 6-well plate into a T25 flask is 2.3-fold. One could calculate easily that in order to cover the bottom surface of one well of a 6-well plate the cells should be divided 5 times (counting from confluent monolayer of one well of a 96-well plate) and have to go through one more mitosis to reach the confluent monolayer in flask T25.

The method of ectopic foci formation has been described previously [18]. In brief, the bone marrow plug was implanted under the renal capsule of non-irradited or irradiated with the dose of 6-10 Gy syngeneic recipient mice. Hematopoiesis in animals irradiated with 10 Gy was carried out by the intravenous injection of syngeneic bone marrow cells (no less than 106 bone marrow cells per mouse). Six weeks later, the size of the developed ectopic foci was measured by the calculation of the number of nucleated cells inside the foci. The number of CFU-F in ectopic foci was measured by the standard method described above.

Statistical analysis was performed using Student's t-test.

Results and discussion

CFU-F is a heterogenic group of stromal precursor cells with different proliferative potential. The concentration of CFU-F per 106 bone marrow cells in non-irradiated and irradiated with 6 Gy mice 1.5 to 3 months before the analysis does not differ significantly (68.4 ± 8.3 versus 80.6 ± 7.4 correspondingly). CFU-F derived colonies from the bone marrow of non-irradiated and sub-lethally irradiated mice after cloning (seeding concentration 30,000 cells per well of the 96-well plate) were sequentially re-transplanted to 24- and 6- well plates, and subsequently to a T25 flask (Fig. 1). Cells from only 30% of CFU-F derived colonies from non-irradiated mice and 6.25% from irradiated ones were able to undergo more than six rounds of mitosis. After irradiation, the proliferative potential of CFU-F decreased while their concentration in the bone marrow did not change. Precursor cells that survived the irradiation filled the concentration of CFU-F in the bone marrow that resulted in the exhaustion of precursors with high enough proliferative potential. On the contrary, after treatment of mice with different cytostatic agents the concentration of CFU-F in the bone marrow decreased dramatically, and even at 6 weeks after the end of treatment the concentration was not restored [19]. Taking into consideration that stromal cells are highly radio-resistant, one could suggest that CFU-F regenerate after irradiation much more efficiently than after cytostatics.

2008-2-en-Shipounova-et-al-MSC-Figure-1.jpg


Figure 1. Proportion of CFU-F derived colonies from bone marrow of non-irradiated and irradiated mice which are able to grow to the confluent monolayer in different culture ware.


Data are shown as the means (±SEM).
Axis of abscissa: culture ware
Axis of ordinate: percent of wells that reached confluence

The implantation of confluent monolayers from 9 CFU-F derived colonies, grown in T25 flasks after sequential re-transplantations under the renal capsule of syngeneic recipients, resulted in no foci formation. Therefore, CFU-F derived cells are not able to transfer the hematopoietic microenvironment. Probably only the very rare CD146 positive CFU-F are able to proliferate and differentiate in vivo forming bone marrow hematopoietic microenvironment [13].

CFU-F in ectopic foci has not been characterized yet. The concentration of CFU-F in the ectopic foci turned out to be lower than in the bone marrow (Fig. 2А). The concentration of CFU-F in ectopic foci formed in irradiated recipients was reduced 20-fold in comparison with foci formed in non-irradiated recipients. As the size of the foci in irradiated recipients is enlarged significantly (Fig. 2B), the actual number of CFU-F in such foci is only 3-fold lower than in foci formed in non-irradiated recipients (Fig. 2C).

2008-2-en-Shipounova-et-al-MSC-Figure-2A.jpg


Figure 2. CFU-F in the ectopic foci formed in non-irradiated and irradiated recipients.

А. Concentration of CFU-F in the ectopic foci and bone marrow of non-irradiated mice.om bone marrow of non-irradiated and irradiated mice which are able to grow to the confluent monolayer in different culture ware.


Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of CFU-F per 106 cells

2008-2-en-Shipounova-et-al-MSC-Figure-2B.jpg


B. The size of ectopic foci formed in non-irradiated and irradiated recipients.


Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of nucleated cells in the foci, х 106

2008-2-en-Shipounova-et-al-MSC-Figure-2C.jpg

C. CFU-F number in the ectopic foci.

Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of CFU-F per foci


Thus, it is possible to suggest that the position of CFU-F in the hierarchy of MSC is higher than the position of SMP, but lower than MSC.

Stromal growth factor produced by bones of irradiated recipients induces the formation of enlarged foci and has been shown to persist in blood [20]. Addition of murine sera to CFU-F cultivation media increased their number [21]. However, addition of 2.5% of sera from irradiated mice to cultivation media for CFU-F decreased their number dramatically (Fig. 3). A high number of separate cells that were not producing clones could be seen on the flask bottom, which is atypical for the method and the mode of CFU-F growth. One could suggest several causes for the decreasing CFU-F number in the presence of sera from irradiated mice. It is impossible to neglect the difficulties in CFU-F against the background of a multitude of separate cells revealed after the addition of sera from irradiated mice. On the other hand, stromal growth factor from this serum obviously stimulated the differentiation of CFU-F progeny, as if inducing hematopoietic territory as it happens in vivo during the development of hematopoietic ectopic foci in irradiated recipients. The in vitro decrease of CFU-F concentration in this case is also analogous to the results obtained in vivo. Therefore, the data concerning the effect of the addition of sera from irradiated mice on CFU-F growth also supports the proposed positions of SMP and CFU-F in the hierarchy of MSC.

2008-2-en-Shipounova-et-al-MSC-Figure-3.jpg


Figure 3. Effect of sera from non-irradiated and irradiated mice on the number of CFU-F.


Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of CFU-F per 106 cell

Analysis of the total data positioned CFU-F in the hierarchy of stromal precursor cells (Fig. 4). These heterogenic groups are not able to self-renew, but their high proliferative potential is the result of being the progeny of MSC. SMP, stimulated by stromal growth factor, enlarges the hematopoietic territory in irradiated recipients and takes place at a lower position than CFU-F. There is still a lot of research that needs to be done regarding the hierarchy of MSC.

Figure 4. Hierarchy of MSC

2008-2-en-Shipounova-et-al-MSC-Figure-4.jpg

Acknowledgements

This study was supported by Grant 07-04-00183-а of Russian Fund of Fundamental science.

References

1. Caplan AI. The mesengenic process. Clin Plast Surg. 1994;21:429-435.

2. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, and Keating A. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy. 2005;7:393-395.

3. Chertkov JL and Gurevitch OA. Self-maintenance ability and kinetics of haemopoietic stroma precursors. Cell Tissue Kinet. 1980;13:535-541.

4. Short B, Brouard N, Occhiodoro-Scott T, Ramakrishnan A, and Simmons PJ. Mesenchymal stem cells. Arch Med Res. 2003;34:565-571.

5. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, and Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315-317.

6. Bae S, Park CW, Son HK, Ju HK, Paik D, Jeon CJ, Koh GY, Kim J, and Kim H. Fibroblast activation protein alpha identifies mesenchymal stromal cells from human bone marrow. Br J Haematol. 2008;142:827-830.

7. Friedenstein AJ, Chailakhjan RK, and Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 1970;3:393-403.

8. Castro-Malaspina H, Gay RE, Jhanwar SC, Hamilton JA, Chiarieri DR, Meyers PA, Gay S, and Moore MA. Characteristics of bone marrow fibroblast colony-forming cells (CFU-F) and their progeny in patients with myeloproliferative disorders. Blood. 1982;59:1046-1054.

9. Koide Y, Morikawa S, Mabuchi Y, Muguruma Y, Hiratsu E, Hasegawa K, Kobayashi M, Ando K, Kinjo K, Okano H, and Matsuzaki Y. Two distinct stem cell lineages in murine bone marrow. Stem Cells. 2007;25:1213-1221.

10. Owen M and Friedenstein AJ. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found Symp. 1988;136:42-60.

11. Friedenstein AJ, Chailakhyan RK, and Gerasimov UV. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet. 1987;20:263-272.

12. Bennett JH, Joyner CJ, Triffitt JT, and Owen ME.  Adipocytic cells cultured from marrow have osteogenic potential. J Cell Sci. 1991;99(Pt 1): 131-139.

13. Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, Tagliafico E, Ferrari S, Robey PG, Riminucci M, and Bianco P. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell. 2007;131:324-336.

14. Ylostalo J, Bazhanov N, and Prockop DJ. Reversible commitment to differentiation by human multipotent stromal cells in single-cell-derived colonies. Exp Hematol. 2008.

15. Kuznetsov SA, Friedenstein AJ, and Robey PG. Factors required for bone marrow stromal fibroblast colony formation in vitro. Br J Haematol. 1997;97:561-570.

16. Kaneko S, Motomura S, and Ibayashi H. Differentiation of human bone marrow-derived fibroblastoid colony forming cells (CFU-F) and their roles in haemopoiesis in vitro. Br J Haematol. 1982;51:217-225.

17. Chertkov JL and Gurevitch OA. Radiosencitivity of precursors of hematopoietic microenvironment. Radiat Res. 1979;79:177-186.

18. Chertkov JL and Gurevitch OA. Hematopoietic stem cell and its microenvironment. Moscow: Meditzina; 1984.

19. Nifontova I, Svinareva D, Petrova T, and Drize N. Sensitivity of Mesenchymal Stem Cells and Their Progeny to Medicines Used for the Treatment of Hematoproliferative Diseases. Acta Haematol. 2008;119:98-103.

20. Drize NI, Ershler MA, and Chertkov IL. Radiation-induced hemopoietic cell growth factor: detection in a culture. Bull Exp Biol Med. 2001;132:1213-1215.

21. Abe R, Donnelly SC, Peng T, Bucala R, and Metz CN. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol. 2001;166:7556-7562.


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Introduction

Stromal cells of the hematopoietic microenvironment are the progeny of mesenchymal stem cells (MSC). MSC are non-hematopoietic multipotent stem cells able to differentiate into different cells lines, such as osteoblasts, adipocytes, chondrocytes, fibroblasts, and other cell lines [1]. The ability to self-renew has not been proven for human MSC [2]; however, these cells are known to have high proliferative potential when cultured. Murine MSC are able to transfer a hematopoietic microenvironment in vivo at least 9 times, confirming their ability for self-maintenance [3]. Until now, the data about phenotypical markers of MSC has not been developed sufficiently [4], but MSC are able to express the number of non-specific markers [5]. It was shown recently that fibroblast activation protein perfectly identifies mesenchymal stromal cells [6]. The compartment of stromal precursor cells can be characterized by physiological methods according to the first 25 years of hematopoietic stem cells (HSC) research. Explantation of bone marrow cell suspension into culture flasks led to the development of discrete fibroblast-like colonies. Each colony represents a clone produced by single clonogenic precursor cells–colony-forming unit fibroblasts (CFU-F) [7]. CFU-F are of mesenchymal origin and do not develop from HSC [8, 9]. CFU-F are heterogenic cell populations and some of them possess high proliferative potential; their ability to differentiate could be associated with MSC [10]. The transplantation of the pull of colonies into the organism leads to the development of different tissues, including bone and adipose tissues [11, 12]. The comparison of CFU-F with MSC is questionable because CFU-F are able to differentiate inside the diffusion chambers after implantation to the organism, but it is not known whether they are able to transfer the full microenvironment or self-maintain. Recent data suggests that CD146+ CFU-F with high proliferative capacity, are able to transfer the microenvironment, but this can be applied only to rare cells in the bone marrow [13]. Moreover, human multipotent stromal cells readily form single-cell-derived colonies, which are heterogeneous because cells from a colony form new colonies that vary in size and differentiation potential [14]. Several growth factors influence the CFU-F growth, and four of them are necessary for CFU-F development: PDGF, bFGF, TGFβ and EGF [15]. The proliferative potential of CFU-F is not studied in detail, but it is known that most of the CFU-F in the organism are not cycling and remain in the “Go” phase [16]. However, CFU-F start to proliferate when transferred to cultures.

The compartments of MSC and HSC have hierarchical structures. This is well known for HSC, but in the case of MSC it was discovered for the first time in experiments with ectopic foci formation in vivo. At 6 weeks after implantation of the donor bone marrow plug under the renal capsule of the syngeneic recipient, ectopic hematopoietic foci developed at the site of transplantation. In such foci, stromal cells belong to the donor, and hematopoietic cells belong to the recipient. Multiple histological examinations during foci formation have revealed that the hematopoietic microenvironment was built de novo. The method of ectopic foci formation is not only qualitative, but also quantitative. The size of the hematopoietic territory is defined by the number of MSCs transplanted, and restricted accordingly to the number of niches transferred with the bone marrow plug; since the foci size is proportional to the amount of implanted bone marrow. It is possible to transfer the foci under the renal capsule of the secondary recipient. In this case foci again would be built de novo due to the presence of MSC. The foci sustain at least 9 re-transplantations that prove the high capability of MSC to self-renew [3]. The radio-sensitivity of MSC is much lower than that of HSC [17]. In summarizing this data it is possible to conclude that stromal precursor cells that are able to transfer the microenvironment are true stem cells and the method of ectopic foci formation allows the opportunity to estimate their numbers in bone marrow.

In irradiated recipients foci formed after the implantation of bone marrow plugs are enlarged 2-3 fold in comparison with foci developed in non-irradiated mice. However, the re-transplantation of these enlarged foci to non-irradiated recipients led to the formation of foci of normal size. Thus, in the enlarged foci the number of MSC do not increase, and the microenvironment created in the irradiated recipients is enlarged by cells other than MSC inducible precursor cells, which are not able to self-renew [18]. Such stromal multipotent precursor (SMP) cells have the position in the hierarchy of MSC similar to the position of the multipotent precursor in the hierarchy of HSC. The position of CFU-F in the hierarchy of MSC is unknown. It is possible to define it by studying the concentration of CFU-F in ectopic foci formed in non-irradiated and irradiated recipients. There are three possible variants for the irradiated recipients: the concentration of CFU-F could increase, decrease, or remain unchanged. We suppose that CFU-F could be considered to be the progeny of SMP in cases where their concentration in enlarged foci do not change and their numbers increase 2-3 fold according to the foci size. In cases of both decreased concentration and number of CFU-F in enlarged foci, it is possible to assume that these precursor cells with limited proliferative potential are used irreversibly to form SMP, thus CFU-F are located higher than SMP in the hierarchy of MSC and have the position directly before SMP. If the actual number of CFU-F in the enlarged foci do not change, one could conclude that there are precursors that do not take part in the formation of the microenvironment and represent special populations of stromal clonogenic cells.

The measurement of the concentration and number of CFU-F in ectopic foci in irradiated and non-irradiated recipients performed in this study defines the position of CFU-F immediately after MSC and before SMP in the hierarchy of mesenchymal stem cells.

Materials and methods

The hybrid mice (СВАхC57Bl/6) F1 at the age of 12-16 weeks at the beginning of the experiment were used. The animals were irradiated on the IPK 137Cs irradiator with a dose rate of 16 сGy/min.

For CFU-F analysis 106 bone marrow cells were seeded into the T25 flask in 5 ml αМЕМ (ICN) with 20% fetal bovine serum (Hyclone) and 5 ng/ml basic Fibroblast Growth Factor (bFGF) (donated by Gasparian M.E., Lab. of Protein engineering, IBC, RAS). Cells were cultivated for 14 days in 370С and 5% СО2. Formed colonies were stained with 0.1% crystal violet on 20% methanol and counted under the inverted microscope (the colony was counted if it contained no less than 50 cells).

For cloning of individual CFU-F, bone marrow cells were planted into a 96-well plate in concentrations from 30,000 to 50,000 of nucleated cells per well in standard media. In this cultivation system the most convenient concentration turned out to be 30,000 cells per well (Table 1). In this assay the frequency of CFU-F was calculated by means of the Poisson equation:

2008-2-en-Shipounova-et-al-MSC-Equation.jpg

Table 1. Frequency of CFU-F in the bone marrow of mice

2008-2-en-Shipounova-et-al-MSC-Table-1.jpg

Clones from the wells containing single colonies were transferred into 24-well plates, then into 6-well plates, and finally into T25 flasks. For each procedure, the cells were washed with Versen solution and detached with 0.25% tripsin solution. The proliferative potential of CFU-F was estimated by their ability to form a confluent monolayer during sequential transfers from small to large available growth areas. The number of divisions performed by CFU-F progeny was evaluated by the assumption that the number of cells in the confluent monolayer increases proportionally to the growth area. For instance, the bottom square of the well in a 96-well plate is 0.32 cm2; 24-well, 1.88 cm2; 6-well, 9.4 cm2; and a Т25 flask is 25 cm2. If the confluent monolayer is transferred from one well of a 96-well plate into one well of a 24-well plate, the size of available growth area increases 6-fold; from a 24-well plate to a 6-well plate is 5-fold; and from a 6-well plate into a T25 flask is 2.3-fold. One could calculate easily that in order to cover the bottom surface of one well of a 6-well plate the cells should be divided 5 times (counting from confluent monolayer of one well of a 96-well plate) and have to go through one more mitosis to reach the confluent monolayer in flask T25.

The method of ectopic foci formation has been described previously [18]. In brief, the bone marrow plug was implanted under the renal capsule of non-irradited or irradiated with the dose of 6-10 Gy syngeneic recipient mice. Hematopoiesis in animals irradiated with 10 Gy was carried out by the intravenous injection of syngeneic bone marrow cells (no less than 106 bone marrow cells per mouse). Six weeks later, the size of the developed ectopic foci was measured by the calculation of the number of nucleated cells inside the foci. The number of CFU-F in ectopic foci was measured by the standard method described above.

Statistical analysis was performed using Student's t-test.

Results and discussion

CFU-F is a heterogenic group of stromal precursor cells with different proliferative potential. The concentration of CFU-F per 106 bone marrow cells in non-irradiated and irradiated with 6 Gy mice 1.5 to 3 months before the analysis does not differ significantly (68.4 ± 8.3 versus 80.6 ± 7.4 correspondingly). CFU-F derived colonies from the bone marrow of non-irradiated and sub-lethally irradiated mice after cloning (seeding concentration 30,000 cells per well of the 96-well plate) were sequentially re-transplanted to 24- and 6- well plates, and subsequently to a T25 flask (Fig. 1). Cells from only 30% of CFU-F derived colonies from non-irradiated mice and 6.25% from irradiated ones were able to undergo more than six rounds of mitosis. After irradiation, the proliferative potential of CFU-F decreased while their concentration in the bone marrow did not change. Precursor cells that survived the irradiation filled the concentration of CFU-F in the bone marrow that resulted in the exhaustion of precursors with high enough proliferative potential. On the contrary, after treatment of mice with different cytostatic agents the concentration of CFU-F in the bone marrow decreased dramatically, and even at 6 weeks after the end of treatment the concentration was not restored [19]. Taking into consideration that stromal cells are highly radio-resistant, one could suggest that CFU-F regenerate after irradiation much more efficiently than after cytostatics.

2008-2-en-Shipounova-et-al-MSC-Figure-1.jpg


Figure 1. Proportion of CFU-F derived colonies from bone marrow of non-irradiated and irradiated mice which are able to grow to the confluent monolayer in different culture ware.


Data are shown as the means (±SEM).
Axis of abscissa: culture ware
Axis of ordinate: percent of wells that reached confluence

The implantation of confluent monolayers from 9 CFU-F derived colonies, grown in T25 flasks after sequential re-transplantations under the renal capsule of syngeneic recipients, resulted in no foci formation. Therefore, CFU-F derived cells are not able to transfer the hematopoietic microenvironment. Probably only the very rare CD146 positive CFU-F are able to proliferate and differentiate in vivo forming bone marrow hematopoietic microenvironment [13].

CFU-F in ectopic foci has not been characterized yet. The concentration of CFU-F in the ectopic foci turned out to be lower than in the bone marrow (Fig. 2А). The concentration of CFU-F in ectopic foci formed in irradiated recipients was reduced 20-fold in comparison with foci formed in non-irradiated recipients. As the size of the foci in irradiated recipients is enlarged significantly (Fig. 2B), the actual number of CFU-F in such foci is only 3-fold lower than in foci formed in non-irradiated recipients (Fig. 2C).

2008-2-en-Shipounova-et-al-MSC-Figure-2A.jpg


Figure 2. CFU-F in the ectopic foci formed in non-irradiated and irradiated recipients.

А. Concentration of CFU-F in the ectopic foci and bone marrow of non-irradiated mice.om bone marrow of non-irradiated and irradiated mice which are able to grow to the confluent monolayer in different culture ware.


Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of CFU-F per 106 cells

2008-2-en-Shipounova-et-al-MSC-Figure-2B.jpg


B. The size of ectopic foci formed in non-irradiated and irradiated recipients.


Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of nucleated cells in the foci, х 106

2008-2-en-Shipounova-et-al-MSC-Figure-2C.jpg

C. CFU-F number in the ectopic foci.

Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of CFU-F per foci


Thus, it is possible to suggest that the position of CFU-F in the hierarchy of MSC is higher than the position of SMP, but lower than MSC.

Stromal growth factor produced by bones of irradiated recipients induces the formation of enlarged foci and has been shown to persist in blood [20]. Addition of murine sera to CFU-F cultivation media increased their number [21]. However, addition of 2.5% of sera from irradiated mice to cultivation media for CFU-F decreased their number dramatically (Fig. 3). A high number of separate cells that were not producing clones could be seen on the flask bottom, which is atypical for the method and the mode of CFU-F growth. One could suggest several causes for the decreasing CFU-F number in the presence of sera from irradiated mice. It is impossible to neglect the difficulties in CFU-F against the background of a multitude of separate cells revealed after the addition of sera from irradiated mice. On the other hand, stromal growth factor from this serum obviously stimulated the differentiation of CFU-F progeny, as if inducing hematopoietic territory as it happens in vivo during the development of hematopoietic ectopic foci in irradiated recipients. The in vitro decrease of CFU-F concentration in this case is also analogous to the results obtained in vivo. Therefore, the data concerning the effect of the addition of sera from irradiated mice on CFU-F growth also supports the proposed positions of SMP and CFU-F in the hierarchy of MSC.

2008-2-en-Shipounova-et-al-MSC-Figure-3.jpg


Figure 3. Effect of sera from non-irradiated and irradiated mice on the number of CFU-F.


Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of CFU-F per 106 cell

Analysis of the total data positioned CFU-F in the hierarchy of stromal precursor cells (Fig. 4). These heterogenic groups are not able to self-renew, but their high proliferative potential is the result of being the progeny of MSC. SMP, stimulated by stromal growth factor, enlarges the hematopoietic territory in irradiated recipients and takes place at a lower position than CFU-F. There is still a lot of research that needs to be done regarding the hierarchy of MSC.

Figure 4. Hierarchy of MSC

2008-2-en-Shipounova-et-al-MSC-Figure-4.jpg

Acknowledgements

This study was supported by Grant 07-04-00183-а of Russian Fund of Fundamental science.

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Шипунова (Нифонтова) И. Н., Свинарева Д. А., Чертков И. Л., Дризе Н. И.

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В работе изучали иерархию стромальных предшественников. Известно, что при переносе костномозгового цилиндра под капсулу почки сингенных мышей очаг эктопического кроветворения образуется за счет мезенхимных стволовых клеток (МСК) донора.
У облученных реципиентов образуется очаг в 2-3 раза большего размера за счет «индуцибельных» предшественников, более дифференцированных по сравнению с МСК. Наряду с упомянутыми тестами in vivo, широко применяется метод оценки концентрации клоногенных стромальных предшественников в культуре (колониеобразующих единиц фибробластных, КОЕф). Однако, взаимное расположение описанных клеток-предшественников в иерархии стромальных стволовых клеток неясно. В работе было проанализировано изменение количества указанных предшественников в очагах, образующихся у облученных реципиентов. Показано, что КОЕф являются самыми близкими из известных на сегодняшний день потомками МСК, а «индуцибельные» предшественники – мультипотентные стромальные предшественники находятся ниже в иерархии и являются клетками, непосредственно увеличивающими размер кроветворной территории в облученных реципиентах.

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Irina Shipounova (Nifontova), Daria Svinareva, Josef Chertkov, Nina Drize

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The hierarchy of stromal precursors is the focus of this research. It has been previously shown that transplantation of the bone marrow plug under the renal capsule of the syngeneic animal leads to the formation of the foci of ectopic hematopoiesis, where a stromal microenvironment is formed by the donor's mesenchymal stem cells (MSC). In the irradiated recipients such foci are 2-3 times larger than in non-irradiated foci due to "inducible" precursors that are more differentiated than MSC. Along with the in vivo tests, the method of in vitro estimation of concentration of clonogenic stromal precursors (CFU-F) is widely used. However, the hierarchical arrangement of the described precursors is still unclear. This study describes the alterations in the number of mentioned precursors in the ectopic hematopoietic foci formed in the irradiated recipients. CFU-F was shown to be the closest MSC progeny thus far, while "inducible" precursor cells – stromal multipotent precursors – are at a lower position in the hierarchy and possibly enlarge the hematopoietic territory in the irradiated recipients directly.

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Irina Shipounova (Nifontova), Daria Svinareva, Josef Chertkov, Nina Drize

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Irina Shipounova (Nifontova), Daria Svinareva, Josef Chertkov, Nina Drize

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The hierarchy of stromal precursors is the focus of this research. It has been previously shown that transplantation of the bone marrow plug under the renal capsule of the syngeneic animal leads to the formation of the foci of ectopic hematopoiesis, where a stromal microenvironment is formed by the donor's mesenchymal stem cells (MSC). In the irradiated recipients such foci are 2-3 times larger than in non-irradiated foci due to "inducible" precursors that are more differentiated than MSC. Along with the in vivo tests, the method of in vitro estimation of concentration of clonogenic stromal precursors (CFU-F) is widely used. However, the hierarchical arrangement of the described precursors is still unclear. This study describes the alterations in the number of mentioned precursors in the ectopic hematopoietic foci formed in the irradiated recipients. CFU-F was shown to be the closest MSC progeny thus far, while "inducible" precursor cells – stromal multipotent precursors – are at a lower position in the hierarchy and possibly enlarge the hematopoietic territory in the irradiated recipients directly.

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The hierarchy of stromal precursors is the focus of this research. It has been previously shown that transplantation of the bone marrow plug under the renal capsule of the syngeneic animal leads to the formation of the foci of ectopic hematopoiesis, where a stromal microenvironment is formed by the donor's mesenchymal stem cells (MSC). In the irradiated recipients such foci are 2-3 times larger than in non-irradiated foci due to "inducible" precursors that are more differentiated than MSC. Along with the in vivo tests, the method of in vitro estimation of concentration of clonogenic stromal precursors (CFU-F) is widely used. However, the hierarchical arrangement of the described precursors is still unclear. This study describes the alterations in the number of mentioned precursors in the ectopic hematopoietic foci formed in the irradiated recipients. CFU-F was shown to be the closest MSC progeny thus far, while "inducible" precursor cells – stromal multipotent precursors – are at a lower position in the hierarchy and possibly enlarge the hematopoietic territory in the irradiated recipients directly.

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Н., Свинарева Д. А., Чертков И. Л., Дризе Н. И.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(138) "

Шипунова (Нифонтова) И. Н., Свинарева Д. А., Чертков И. Л., Дризе Н. И.

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Шипунова (Нифонтова) И. Н., Свинарева Д. А., Чертков И. Л., Дризе Н. И.

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["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11403" ["VALUE"]=> string(3) "833" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "833" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(53) "Nina Drize" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" 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Известно, что при переносе костномозгового цилиндра под капсулу почки сингенных мышей очаг эктопического кроветворения образуется за счет мезенхимных стволовых клеток (МСК) донора. <br>У облученных реципиентов образуется очаг в 2-3 раза большего размера за счет «индуцибельных» предшественников, более дифференцированных по сравнению с МСК. Наряду с упомянутыми тестами in vivo, широко применяется метод оценки концентрации клоногенных стромальных предшественников в культуре (колониеобразующих единиц фибробластных, КОЕф). Однако, взаимное расположение описанных клеток-предшественников в иерархии стромальных стволовых клеток неясно. В работе было проанализировано изменение количества указанных предшественников в очагах, образующихся у облученных реципиентов. Показано, что КОЕф являются самыми близкими из известных на сегодняшний день потомками МСК, а «индуцибельные» предшественники – мультипотентные стромальные предшественники находятся ниже в иерархии и являются клетками, непосредственно увеличивающими размер кроветворной территории в облученных реципиентах.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2116) "

В работе изучали иерархию стромальных предшественников. Известно, что при переносе костномозгового цилиндра под капсулу почки сингенных мышей очаг эктопического кроветворения образуется за счет мезенхимных стволовых клеток (МСК) донора.
У облученных реципиентов образуется очаг в 2-3 раза большего размера за счет «индуцибельных» предшественников, более дифференцированных по сравнению с МСК. Наряду с упомянутыми тестами in vivo, широко применяется метод оценки концентрации клоногенных стромальных предшественников в культуре (колониеобразующих единиц фибробластных, КОЕф). Однако, взаимное расположение описанных клеток-предшественников в иерархии стромальных стволовых клеток неясно. В работе было проанализировано изменение количества указанных предшественников в очагах, образующихся у облученных реципиентов. Показано, что КОЕф являются самыми близкими из известных на сегодняшний день потомками МСК, а «индуцибельные» предшественники – мультипотентные стромальные предшественники находятся ниже в иерархии и являются клетками, непосредственно увеличивающими размер кроветворной территории в облученных реципиентах.

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В работе изучали иерархию стромальных предшественников. Известно, что при переносе костномозгового цилиндра под капсулу почки сингенных мышей очаг эктопического кроветворения образуется за счет мезенхимных стволовых клеток (МСК) донора.
У облученных реципиентов образуется очаг в 2-3 раза большего размера за счет «индуцибельных» предшественников, более дифференцированных по сравнению с МСК. Наряду с упомянутыми тестами in vivo, широко применяется метод оценки концентрации клоногенных стромальных предшественников в культуре (колониеобразующих единиц фибробластных, КОЕф). Однако, взаимное расположение описанных клеток-предшественников в иерархии стромальных стволовых клеток неясно. В работе было проанализировано изменение количества указанных предшественников в очагах, образующихся у облученных реципиентов. Показано, что КОЕф являются самыми близкими из известных на сегодняшний день потомками МСК, а «индуцибельные» предшественники – мультипотентные стромальные предшественники находятся ниже в иерархии и являются клетками, непосредственно увеличивающими размер кроветворной территории в облученных реципиентах.

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Introduction

Multipotent mesenchymal stromal cells (MSC), also named mesenchymal stem cells, are characterized by adherence to plastic when maintained in standard cultures in vitro, by expression of surface antigens CD105 and CD90 but lack of hematopoietic markers CD34 and CD45, and by differentiation into osteoblasts, adipocytes and chondroblasts in vitro [1]. Since their first description [2], a multitude of work has been carried out to show their properties and functionality in vitro and in vivo [3, 4, 5]. MSC have been shown to display a considerable therapeutic potential in pre-clinical [6-11] and clinical [12-16] studies for the treatment/regeneration of neuronal degeneration, osteogenesis imperfecta, graft-versus-host disease, support of hematopoietic engraftment, metabolic diseases, and bone and cartilage tissues, as well as renal and myocardial infarction. To date, all reported clinical trials are employing hMSC generated in medium supplemented with fetal calf serum (FCS). FCS, however, is a source of undesirable xenogeneic antigens, and carries the risk of transmitting animal viral, prion and zoonose contaminations. Additionally, FCS has been implicated with anaphylactic or arthus-like immune reactions in patients who received cells generated in FCS-supplemented medium [17], even leading to arrhythmias after cellular cardioplasty [18]. Uptake of FCS components is an active process [19]. Although up to 99.99% of FCS can be removed by sequential cultivation of MSC first in FCS, followed by autologous or heterologous serum [20], a residual risk still remains.

Very recently, human platelet lysates (PL) have been shown to serve as a safe substitute for animal serum for hMSC expansion [21-23], but the resulting hMSC are still not fully characterized. We have extensively analyzed animal-serum free culture conditions for hMSC expansion using platelet lysate as a substitute for FCS. Compared to FCS-supplemented culture conditions, we found a significant increase of both CFU-F as well as cumulative cell numbers after expansion. Our optimized protocol uses 5% of PL as growth supplement. Cells obtained by this protocol meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. MSC retained their immune-privileged potential by suppressing the allogeneic reaction of T-cells. Additionally, gene expression profiles showed decreased mRNA levels of MHC II components. Taken together, our GMP-compatible protocol allows for safe and accelerated expansion of hMSC, which could be of interest for cell and tissue therapies.

Results and discussion

In comparing the additives FCS and PL, the media used consisted of α-MEM containing glutamax, the stable form of glutamine, supplemented either with + 10% preselected fetal calf serum (FCS; BioWhittaker, Apen, Germany) + 1% glutamine or 5% freshly thawed platelet lysate (PL) + 10 IU Heparin (Roche, Grenzach-Wylen, Germany; 5000 IU/ml) per 5 ml medium. The isolation of hMSC already revealed a higher number of CFU-F in PL-containing medium (Table 1) as well as larger colonies (Figure 1). In line with the CFU-F numbers, the expansion capabilities of hMSC grown in PL were considerably higher (Figure 2), reaching twice as many cells after only 40 days. With regard to morphology, a more elongated cell appearance has been observed in PL-cultures, resulting in significantly higher cell numbers per growth area.

Table 1. Isolation of hMSC with FCS- or PL-supplemented media.
Values are shown for 107 plated cells.

2008-2-en-Lange-et-al-Table-1.jpg

Figure 1. Isolation of hMSC by plating 5 x 105 mononuclear cells/well in 3 ml.
Shown are crystal violet-stained CFU-F in FCS- or PL-supplemented media 14 days after seeding.

2008-2-en-Lange-et-al-Figure-1.jpg

Figure 2. Accelerated expansion of MSC in PL- compared to FCS-containing medium αMEM.
Shown are cumulative cell numbers of one example out of 11 experiments. Each symbol respresents a single time point of trypsinization.

2008-2-en-Lange-et-al-Figure-2.jpg


PL contains 7 fundamental growth factors actively secreted by platelets: PDGF-αα (platelet derived growth factor), -ββ, -αβ, TGF-β1 (transforming growth factor) and -β2, VEGF (vascular endothelial growth factor) and EGF (epidermal growth factor) [24, 25]. The growth factors PDGF, TGF, EGF and FGF (fibroblast growth factor) have been described as mitogens for MSC [4]. Thrombocyte concentrates are regularly produced and applied in everyday clinical life, and meet all criteria for a safe and well-controlled growth factor source. The main reason for the superiority of PL therefore may originate in the release of these factors. We thoroughly analyzed PL with either Human 27-plex (BIO-RAD) or ELISA and showed that inflammatory and anti-inflammatory cytokines as well as a variety of mitogenic factors are contained in PL (Table 2). Previously, it has been shown that thrombocytes release certain amounts of mitogenic cytokines, varying for PDGF-αβ for example, between 35-133 ng/ml [25]. For effective expansion of MSC, an optimized preparation of PL is needed. It consists of pooled PL from at least 10 donors (to equalize for differences in cytokine concentrations) with a minimum concentration of 3 x 109 thrombocytes/ml. Beside this, the accelerated growth under the influence of PL is supported by differential gene expression profile showing an upregulation of cycle-promoting proteins and downregulation of genes for differentiation, attachment, and apoptosis [26].

Table 2. Determination of factor-concentrations in PL. Anti-inflammatory cytokines are shown in bold, inflammatory in italic.
The human-plex method presents the concentration in [pg/ml] from undiluted PL, while in the ELISA PL was diluted to a thrombocyte concentration of 1 x 109/ml and used as 5% in medium (the values therefore have to be multiplied by at least 20). < : below the detection limit.

2008-2-en-Lange-et-al-Table-2.jpg


Evaluation of the surface antigens CD34, CD45, CD59, CD90 and CD105 by flow cytometry revealed a similar phenotype as with FCS-medium, i.e. a lack of the hematopoietic markers CD34 and CD45 and expression of CD59, CD90 and CD105 (not shown). Additionally, both expansion media enabled a subsequent differentiation of hMSC into osteo-, adipo- and chondrogenic lineages. An exception in the quantity of differentiating cells was found for adipogenic differentiation. The formation of adipocytes was delayed and required longer induction times. This result is supported by the downregulation of genes involved in fatty acid metabolism [26]. We assess this decreased adipogenic/lipogenic ability as a favorable property, because in mice the intra-arterial injection of MSC for treatment of chronic kidney injury has revealed formation of adipocytes [27].

MSC have been described as immunomodulatory by impairing T-cell activation without inducing anergy. We tested the immunomodulatory properties of PL-expanded hMSC in vitro in the mixed lymphocyte reaction (MLR). MLRs were carried out with different combinations of allogeneic human peripheral blood mononuclear cells (hPBMC) used as effectors (E) and irradiated stimulators/activators (A) at ratios of 1:1. Human MSC (M) added to the MLR were from unrelated healthy donors. In all 6 experiments, hMSC added at effector/stimulator/MSC ratio of 1:1:1 suppressed T cell proliferation efficiently (p=0.000004). The average inhibition at this ratio was 84.8 ± 9.7% (Figure 3). In contrast to FCS-generated hMSC, no dilution effect of the MSC-effect with decreasing numbers [28] was observed. This result is supported by differential gene expression showing a downregulation of MHC II compounds in hMSC (Figure 4). Addition of PL-generated hMSC leads to significantly decreased immunostimulation of allogeneic T cells caused by MSC. Expanded hMSC express MHC I but not II complexes although MHC II is present intracellularly, and can be induced by addition of interferon gamma (IFN-γ) [29]. The lack of MHC II on hMSC has been interpreted so far as evidence for their non-stimulating properties, so that MSC are transplantable between MHC-incompatible individuals. The downregulation of MHC II in hMSC expanded in PL-supplemented medium makes the cell preparations even more safe and useful for application in cell-replacement therapies. It has been shown that both autologous and allogeneic MSC can be used without significant immune reactions [30, 31, 32] and PL-MSC could make the allogeneic use even safer. We expect, according to the results of decreased allo-stimulation under the influence of PL-MSC, a broader applicability of these MSC.

2008-2-en-Lange-et-al-Figure-3.jpg


Figure 3. Immunomodulatory properties of hMSC are preserved after cultivation in PL-supplemented medium. Bar graph shows the relative percentage of Ki-67+ CD3+ cells in the presence of effector (E), irradiated activator (A), and PL-generated MSCs (M) in various ratios. Data represent relative mean values ± SD of proliferating Ki-67 positive T-cells from 6 experiments.









2008-2-en-Lange-et-al-Figure-4.jpg

Figure 4. Differential gene expression profile reveals the downregulation of MHC II compounds in MSCs cultured in PL- compared to FCS-supplemented media.
Gene expression values are shown as log2 of raw fluorescence for MHC II genes involved in antigen presentation.


Additional gene expression data shows that PL-generated MSCs might be particularly good candidates for regenerative therapy in CNS damage. They express the gene Prickle1, which is involved in neuro-regeneration, to an eight-fold higher degree when compared to MSCs cultured in FCS-supplemented media. Mouse Prickle1 and Prickle2 are expressed in postmitotic neurons and promote neurite outgrowth [33]. Furthermore, MAG (Myelin-associated glycoprotein) is expressed at 13-fold lower amount. MAG is a cell membrane glycoprotein, and may be involved in myelination during nerve regereneration. The lack of recovery after central nervous system injury is caused, in part, by myelin inhibitors including MAG. MAG acts as a neurite outgrowth inhibitor for most neurons tested, but stimulates neurite outgrowth in immature dorsal root ganglion neurons [34]. These differentially regulated genes would favor the use of PL-cultured hMSC for regeneration of neuronal injury. Additionally, the 12-fold higher expression of RAR (retinoid acid receptor) -responsive 1 gene (TIG1) [35], 9-fold higher expression of Keratin 18 [36], 5.7-fold higher expression of the cellular retinol binding protein 1 CRBP1 [37], and Prickle 1 suggest a less tumorigenic phenotype of the MSCs after cultivation in PL-supplemented media.

Conclusions

Isolation and expansion of hMSC using PL as medium supplement allows for rapid generation of high cell amounts within short time. MSC expanded under these conditions fulfill all criteria stated for hMSC. Differential gene expressions support the findings of delayed adipogenesis and favorable immunological properties. Thus, PL-generated hMSC are prime candidates for transplantation as well as regenerative approaches.

Acknowledgement

The work was supported by the Federal Ministry of Education and Research, Contract grant number 13N8904 (HyCelex).

References

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9. Lange C, Togel F, Ittrich H, Clayton F, Nolte-Ernsting C, Zander AR, Westenfelder C.  Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney Int. 2005;68:1613-7.

10. Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 2005;289:F31-42.

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12. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE, Brenner MK. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med. 1999;5: 309-313.

13. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439-1441.

14. Koc ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE, Caplan AI, Lazarus HM. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol. 2000;18:307-316.

15. Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant. 2002;30:215-222.

16. Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, Zhang JJ, Chunhua RZ, Liao LM, Lin S, Sun JP. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol. 2004;94:92-95.

17. Selvaggi TA, Walker RE, Fleisher TA. Development of antibodies to fetal calf serum with arthus-like reactions in human immunodeficiency virus-infected patients given syngeneic lymphocyte infusions. Blood. 1997;89:776-779.

18. Chachques JC, Herreros J, Trainini J, Juffe A, Rendal E, Prosper F, Genovese J. Life-threatening arrhythmias after cellular cardioplasty. Autologous human serum for cell culture avoids the implantation of cardioverter-defibrillators in cellular cardiomyoplasty. Int J Cardiol. 2004;95, Suppl 1:S29-33.

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23. Muller I, Kordowich S, Holzwarth C, Spano C, Isensee G, Staiber A, Viebahn S, Gieseke F, Langer H, Gawaz MP, Horwitz EM, Conte P, Handgretinger R, Dominici M. Animal serum-free culture conditions for isolation and expansion of multipotent mesenchymal stromal cells from human BM. Cytotherapy. 2006;8:437-444.

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28. Fang L, Lange C, Engel M, Zander AR, Fehse B. Sensitive Balance of Suppressing and Activating Effects of MSC on T Cell Proliferation. Transplantation. 2006;82:1370-1373.

29. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003;31:890-896.

30. Poh KK, Sperry E, Young RG, Freyman T, Barringhaus KG, Thompson CA. Repeated direct endomyocardial transplantation of allogeneic mesenchymal stem cells: Safety of a high dose, "off-the-shelf", cellular cardiomyoplasty strategy. Int J Cardiol Aug. 2006;2; [Epub ahead of print]

31. Ringden O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lonnies H, Marschall HU, Dlugosz A, Szakos A, Hassan Z, Omazic B, Aschan J, Barkholt L, Le Blanc K.  Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation. 2006;81:1390-1397.

32. Dai W, Hale SL, Martin BJ, Kuang JQ, Dow JS, Wold LE, Kloner RA. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short- and long-term effects. Circulation. 2005;112:214-223.

33. Okuda H, Miyata S, Mori Y, Tohyama M. FEBS Lett. 2007;581:4754-60.

34. Vyas AA, Patel HV, Fromholt SE, Heffer-Lauc M, Vyas KA, Dang J, Schachner M, Schnaar RL. Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration. Proc Natl Acad Sci U S A. 2002;99:8412-7.

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Introduction

Multipotent mesenchymal stromal cells (MSC), also named mesenchymal stem cells, are characterized by adherence to plastic when maintained in standard cultures in vitro, by expression of surface antigens CD105 and CD90 but lack of hematopoietic markers CD34 and CD45, and by differentiation into osteoblasts, adipocytes and chondroblasts in vitro [1]. Since their first description [2], a multitude of work has been carried out to show their properties and functionality in vitro and in vivo [3, 4, 5]. MSC have been shown to display a considerable therapeutic potential in pre-clinical [6-11] and clinical [12-16] studies for the treatment/regeneration of neuronal degeneration, osteogenesis imperfecta, graft-versus-host disease, support of hematopoietic engraftment, metabolic diseases, and bone and cartilage tissues, as well as renal and myocardial infarction. To date, all reported clinical trials are employing hMSC generated in medium supplemented with fetal calf serum (FCS). FCS, however, is a source of undesirable xenogeneic antigens, and carries the risk of transmitting animal viral, prion and zoonose contaminations. Additionally, FCS has been implicated with anaphylactic or arthus-like immune reactions in patients who received cells generated in FCS-supplemented medium [17], even leading to arrhythmias after cellular cardioplasty [18]. Uptake of FCS components is an active process [19]. Although up to 99.99% of FCS can be removed by sequential cultivation of MSC first in FCS, followed by autologous or heterologous serum [20], a residual risk still remains.

Very recently, human platelet lysates (PL) have been shown to serve as a safe substitute for animal serum for hMSC expansion [21-23], but the resulting hMSC are still not fully characterized. We have extensively analyzed animal-serum free culture conditions for hMSC expansion using platelet lysate as a substitute for FCS. Compared to FCS-supplemented culture conditions, we found a significant increase of both CFU-F as well as cumulative cell numbers after expansion. Our optimized protocol uses 5% of PL as growth supplement. Cells obtained by this protocol meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. MSC retained their immune-privileged potential by suppressing the allogeneic reaction of T-cells. Additionally, gene expression profiles showed decreased mRNA levels of MHC II components. Taken together, our GMP-compatible protocol allows for safe and accelerated expansion of hMSC, which could be of interest for cell and tissue therapies.

Results and discussion

In comparing the additives FCS and PL, the media used consisted of α-MEM containing glutamax, the stable form of glutamine, supplemented either with + 10% preselected fetal calf serum (FCS; BioWhittaker, Apen, Germany) + 1% glutamine or 5% freshly thawed platelet lysate (PL) + 10 IU Heparin (Roche, Grenzach-Wylen, Germany; 5000 IU/ml) per 5 ml medium. The isolation of hMSC already revealed a higher number of CFU-F in PL-containing medium (Table 1) as well as larger colonies (Figure 1). In line with the CFU-F numbers, the expansion capabilities of hMSC grown in PL were considerably higher (Figure 2), reaching twice as many cells after only 40 days. With regard to morphology, a more elongated cell appearance has been observed in PL-cultures, resulting in significantly higher cell numbers per growth area.

Table 1. Isolation of hMSC with FCS- or PL-supplemented media.
Values are shown for 107 plated cells.

2008-2-en-Lange-et-al-Table-1.jpg

Figure 1. Isolation of hMSC by plating 5 x 105 mononuclear cells/well in 3 ml.
Shown are crystal violet-stained CFU-F in FCS- or PL-supplemented media 14 days after seeding.

2008-2-en-Lange-et-al-Figure-1.jpg

Figure 2. Accelerated expansion of MSC in PL- compared to FCS-containing medium αMEM.
Shown are cumulative cell numbers of one example out of 11 experiments. Each symbol respresents a single time point of trypsinization.

2008-2-en-Lange-et-al-Figure-2.jpg


PL contains 7 fundamental growth factors actively secreted by platelets: PDGF-αα (platelet derived growth factor), -ββ, -αβ, TGF-β1 (transforming growth factor) and -β2, VEGF (vascular endothelial growth factor) and EGF (epidermal growth factor) [24, 25]. The growth factors PDGF, TGF, EGF and FGF (fibroblast growth factor) have been described as mitogens for MSC [4]. Thrombocyte concentrates are regularly produced and applied in everyday clinical life, and meet all criteria for a safe and well-controlled growth factor source. The main reason for the superiority of PL therefore may originate in the release of these factors. We thoroughly analyzed PL with either Human 27-plex (BIO-RAD) or ELISA and showed that inflammatory and anti-inflammatory cytokines as well as a variety of mitogenic factors are contained in PL (Table 2). Previously, it has been shown that thrombocytes release certain amounts of mitogenic cytokines, varying for PDGF-αβ for example, between 35-133 ng/ml [25]. For effective expansion of MSC, an optimized preparation of PL is needed. It consists of pooled PL from at least 10 donors (to equalize for differences in cytokine concentrations) with a minimum concentration of 3 x 109 thrombocytes/ml. Beside this, the accelerated growth under the influence of PL is supported by differential gene expression profile showing an upregulation of cycle-promoting proteins and downregulation of genes for differentiation, attachment, and apoptosis [26].

Table 2. Determination of factor-concentrations in PL. Anti-inflammatory cytokines are shown in bold, inflammatory in italic.
The human-plex method presents the concentration in [pg/ml] from undiluted PL, while in the ELISA PL was diluted to a thrombocyte concentration of 1 x 109/ml and used as 5% in medium (the values therefore have to be multiplied by at least 20). < : below the detection limit.

2008-2-en-Lange-et-al-Table-2.jpg


Evaluation of the surface antigens CD34, CD45, CD59, CD90 and CD105 by flow cytometry revealed a similar phenotype as with FCS-medium, i.e. a lack of the hematopoietic markers CD34 and CD45 and expression of CD59, CD90 and CD105 (not shown). Additionally, both expansion media enabled a subsequent differentiation of hMSC into osteo-, adipo- and chondrogenic lineages. An exception in the quantity of differentiating cells was found for adipogenic differentiation. The formation of adipocytes was delayed and required longer induction times. This result is supported by the downregulation of genes involved in fatty acid metabolism [26]. We assess this decreased adipogenic/lipogenic ability as a favorable property, because in mice the intra-arterial injection of MSC for treatment of chronic kidney injury has revealed formation of adipocytes [27].

MSC have been described as immunomodulatory by impairing T-cell activation without inducing anergy. We tested the immunomodulatory properties of PL-expanded hMSC in vitro in the mixed lymphocyte reaction (MLR). MLRs were carried out with different combinations of allogeneic human peripheral blood mononuclear cells (hPBMC) used as effectors (E) and irradiated stimulators/activators (A) at ratios of 1:1. Human MSC (M) added to the MLR were from unrelated healthy donors. In all 6 experiments, hMSC added at effector/stimulator/MSC ratio of 1:1:1 suppressed T cell proliferation efficiently (p=0.000004). The average inhibition at this ratio was 84.8 ± 9.7% (Figure 3). In contrast to FCS-generated hMSC, no dilution effect of the MSC-effect with decreasing numbers [28] was observed. This result is supported by differential gene expression showing a downregulation of MHC II compounds in hMSC (Figure 4). Addition of PL-generated hMSC leads to significantly decreased immunostimulation of allogeneic T cells caused by MSC. Expanded hMSC express MHC I but not II complexes although MHC II is present intracellularly, and can be induced by addition of interferon gamma (IFN-γ) [29]. The lack of MHC II on hMSC has been interpreted so far as evidence for their non-stimulating properties, so that MSC are transplantable between MHC-incompatible individuals. The downregulation of MHC II in hMSC expanded in PL-supplemented medium makes the cell preparations even more safe and useful for application in cell-replacement therapies. It has been shown that both autologous and allogeneic MSC can be used without significant immune reactions [30, 31, 32] and PL-MSC could make the allogeneic use even safer. We expect, according to the results of decreased allo-stimulation under the influence of PL-MSC, a broader applicability of these MSC.

2008-2-en-Lange-et-al-Figure-3.jpg


Figure 3. Immunomodulatory properties of hMSC are preserved after cultivation in PL-supplemented medium. Bar graph shows the relative percentage of Ki-67+ CD3+ cells in the presence of effector (E), irradiated activator (A), and PL-generated MSCs (M) in various ratios. Data represent relative mean values ± SD of proliferating Ki-67 positive T-cells from 6 experiments.









2008-2-en-Lange-et-al-Figure-4.jpg

Figure 4. Differential gene expression profile reveals the downregulation of MHC II compounds in MSCs cultured in PL- compared to FCS-supplemented media.
Gene expression values are shown as log2 of raw fluorescence for MHC II genes involved in antigen presentation.


Additional gene expression data shows that PL-generated MSCs might be particularly good candidates for regenerative therapy in CNS damage. They express the gene Prickle1, which is involved in neuro-regeneration, to an eight-fold higher degree when compared to MSCs cultured in FCS-supplemented media. Mouse Prickle1 and Prickle2 are expressed in postmitotic neurons and promote neurite outgrowth [33]. Furthermore, MAG (Myelin-associated glycoprotein) is expressed at 13-fold lower amount. MAG is a cell membrane glycoprotein, and may be involved in myelination during nerve regereneration. The lack of recovery after central nervous system injury is caused, in part, by myelin inhibitors including MAG. MAG acts as a neurite outgrowth inhibitor for most neurons tested, but stimulates neurite outgrowth in immature dorsal root ganglion neurons [34]. These differentially regulated genes would favor the use of PL-cultured hMSC for regeneration of neuronal injury. Additionally, the 12-fold higher expression of RAR (retinoid acid receptor) -responsive 1 gene (TIG1) [35], 9-fold higher expression of Keratin 18 [36], 5.7-fold higher expression of the cellular retinol binding protein 1 CRBP1 [37], and Prickle 1 suggest a less tumorigenic phenotype of the MSCs after cultivation in PL-supplemented media.

Conclusions

Isolation and expansion of hMSC using PL as medium supplement allows for rapid generation of high cell amounts within short time. MSC expanded under these conditions fulfill all criteria stated for hMSC. Differential gene expressions support the findings of delayed adipogenesis and favorable immunological properties. Thus, PL-generated hMSC are prime candidates for transplantation as well as regenerative approaches.

Acknowledgement

The work was supported by the Federal Ministry of Education and Research, Contract grant number 13N8904 (HyCelex).

References

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string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11582" ["VALUE"]=> array(2) { ["TEXT"]=> string(158) "<p class="Autor">Ланге К., Чакироглу Ф., Шписс А., Каппалло-Оберманн Х., Цандер А. Р.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(136) "

Ланге К., Чакироглу Ф., Шписс А., Каппалло-Оберманн Х., Цандер А. Р.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11583" ["VALUE"]=> array(2) { ["TEXT"]=> string(3672) "<p class="bodytext">Мезенхимные стромальные клетки (МСК) из костного мозга человека являются перспективными кандидатами для новых способов лечения в трансплантационной и регенеративной медицине. Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3650) "

Мезенхимные стромальные клетки (МСК) из костного мозга человека являются перспективными кандидатами для новых способов лечения в трансплантационной и регенеративной медицине. Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.

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Claudia Lange, Figen Cakiroglu, Andrej Spiess, Heike Cappallo-Obermann, Axel R. Zander

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Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

Correspondence:
Claudia Lange, Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany,
E-mail: cllange@spam is baduke.uni-hamburg.de

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Human bone marrow mesenchymal stromal cells (hMSC) are promising candidates for new treatment options in transplant and regenerative medicine. However, most expansion protocols still use fetal calf serum (FCS) as growth factor supplement, which is a potential source of undesirable xenogeneic pathogens. We established an easy and reproducible expansion protocol for hMSC based on the addition of platelet lysate (PL) obtained from human thrombocyte concentrates. Both CFU-F and cumulative cell numbers were significantly increased compared to the conventional FCS-based medium. The generated cells meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. Human MSC expanded with PL revealed favorable immunological properties in vitro. Gene expression profiles showed upregulation of cell cycle and DNA replication genes and downregulation of developmental, differentiation, adipogenic and MHC II genes. Thus, PL provides a safe component for accelerated and safe hMSC expansion.

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Claudia Lange, Figen Cakiroglu, Andrej Spiess, Heike Cappallo-Obermann, Axel R. Zander

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Claudia Lange, Figen Cakiroglu, Andrej Spiess, Heike Cappallo-Obermann, Axel R. Zander

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Human bone marrow mesenchymal stromal cells (hMSC) are promising candidates for new treatment options in transplant and regenerative medicine. However, most expansion protocols still use fetal calf serum (FCS) as growth factor supplement, which is a potential source of undesirable xenogeneic pathogens. We established an easy and reproducible expansion protocol for hMSC based on the addition of platelet lysate (PL) obtained from human thrombocyte concentrates. Both CFU-F and cumulative cell numbers were significantly increased compared to the conventional FCS-based medium. The generated cells meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. Human MSC expanded with PL revealed favorable immunological properties in vitro. Gene expression profiles showed upregulation of cell cycle and DNA replication genes and downregulation of developmental, differentiation, adipogenic and MHC II genes. Thus, PL provides a safe component for accelerated and safe hMSC expansion.

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Human bone marrow mesenchymal stromal cells (hMSC) are promising candidates for new treatment options in transplant and regenerative medicine. However, most expansion protocols still use fetal calf serum (FCS) as growth factor supplement, which is a potential source of undesirable xenogeneic pathogens. We established an easy and reproducible expansion protocol for hMSC based on the addition of platelet lysate (PL) obtained from human thrombocyte concentrates. Both CFU-F and cumulative cell numbers were significantly increased compared to the conventional FCS-based medium. The generated cells meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. Human MSC expanded with PL revealed favorable immunological properties in vitro. Gene expression profiles showed upregulation of cell cycle and DNA replication genes and downregulation of developmental, differentiation, adipogenic and MHC II genes. Thus, PL provides a safe component for accelerated and safe hMSC expansion.

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Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

Correspondence:
Claudia Lange, Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany,
E-mail: cllange@spam is baduke.uni-hamburg.de

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Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

Correspondence:
Claudia Lange, Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany,
E-mail: cllange@spam is baduke.uni-hamburg.de

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Ланге К., Чакироглу Ф., Шписс А., Каппалло-Оберманн Х., Цандер А. Р.

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Ланге К., Чакироглу Ф., Шписс А., Каппалло-Оберманн Х., Цандер А. Р.

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Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3650) "

Мезенхимные стромальные клетки (МСК) из костного мозга человека являются перспективными кандидатами для новых способов лечения в трансплантационной и регенеративной медицине. Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.

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Мезенхимные стромальные клетки (МСК) из костного мозга человека являются перспективными кандидатами для новых способов лечения в трансплантационной и регенеративной медицине. Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.

" } } } }

Review articles on mesenchymal cell therapy

Mesenchymal stem cells: precursor hierarchy

Irina Shipounova (Nifontova), Daria Svinareva, Josef Chertkov, Nina Drize

Platelet lysate for rapid expansion of human mesenchymal stromal cells

Claudia Lange, Figen Cakiroglu, Andrej Spiess, Heike Cappallo-Obermann, Axel R. Zander

Review articles on mesenchymal cell therapy

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Шипунова (Нифонтова) И. Н., Свинарева Д. А., Чертков И. Л., Дризе Н. И.

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В работе изучали иерархию стромальных предшественников. Известно, что при переносе костномозгового цилиндра под капсулу почки сингенных мышей очаг эктопического кроветворения образуется за счет мезенхимных стволовых клеток (МСК) донора.
У облученных реципиентов образуется очаг в 2-3 раза большего размера за счет «индуцибельных» предшественников, более дифференцированных по сравнению с МСК. Наряду с упомянутыми тестами in vivo, широко применяется метод оценки концентрации клоногенных стромальных предшественников в культуре (колониеобразующих единиц фибробластных, КОЕф). Однако, взаимное расположение описанных клеток-предшественников в иерархии стромальных стволовых клеток неясно. В работе было проанализировано изменение количества указанных предшественников в очагах, образующихся у облученных реципиентов. Показано, что КОЕф являются самыми близкими из известных на сегодняшний день потомками МСК, а «индуцибельные» предшественники – мультипотентные стромальные предшественники находятся ниже в иерархии и являются клетками, непосредственно увеличивающими размер кроветворной территории в облученных реципиентах.

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Irina Shipounova (Nifontova), Daria Svinareva, Josef Chertkov, Nina Drize

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The hierarchy of stromal precursors is the focus of this research. It has been previously shown that transplantation of the bone marrow plug under the renal capsule of the syngeneic animal leads to the formation of the foci of ectopic hematopoiesis, where a stromal microenvironment is formed by the donor's mesenchymal stem cells (MSC). In the irradiated recipients such foci are 2-3 times larger than in non-irradiated foci due to "inducible" precursors that are more differentiated than MSC. Along with the in vivo tests, the method of in vitro estimation of concentration of clonogenic stromal precursors (CFU-F) is widely used. However, the hierarchical arrangement of the described precursors is still unclear. This study describes the alterations in the number of mentioned precursors in the ectopic hematopoietic foci formed in the irradiated recipients. CFU-F was shown to be the closest MSC progeny thus far, while "inducible" precursor cells – stromal multipotent precursors – are at a lower position in the hierarchy and possibly enlarge the hematopoietic territory in the irradiated recipients directly.

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Mesenchymal stem cells: precursor hierarchy

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Irina Shipounova (Nifontova), Daria Svinareva, Josef Chertkov, Nina Drize

The hierarchy of stromal precursors is the focus of this research. It has been previously shown that transplantation of the bone marrow plug under the renal capsule of the syngeneic animal leads to the formation of the foci of ectopic hematopoiesis, where a stromal microenvironment is formed by the donor's mesenchymal stem cells (MSC). In the irradiated recipients such foci are 2-3 times larger than in non-irradiated foci due to "inducible" precursors that are more differentiated than MSC. Along with the in vivo tests, the method of in vitro estimation of concentration of clonogenic stromal precursors (CFU-F) is widely used. However, the hierarchical arrangement of the described precursors is still unclear. This study describes the alterations in the number of mentioned precursors in the ectopic hematopoietic foci formed in the irradiated recipients. CFU-F was shown to be the closest MSC progeny thus far, while "inducible" precursor cells – stromal multipotent precursors – are at a lower position in the hierarchy and possibly enlarge the hematopoietic territory in the irradiated recipients directly.

Review articles on mesenchymal cell therapy

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Ланге К., Чакироглу Ф., Шписс А., Каппалло-Оберманн Х., Цандер А. Р.

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Авторы [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_RU] => Array ( [ID] => 26 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Организации [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 26 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => [VALUE] => [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 11583 [VALUE] => Array ( [TEXT] => <p class="bodytext">Мезенхимные стромальные клетки (МСК) из костного мозга человека являются перспективными кандидатами для новых способов лечения в трансплантационной и регенеративной медицине. Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Мезенхимные стромальные клетки (МСК) из костного мозга человека являются перспективными кандидатами для новых способов лечения в трансплантационной и регенеративной медицине. Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Описание/Резюме [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [DOI] => Array ( [ID] => 28 [TIMESTAMP_X] => 2016-04-06 14:11:12 [IBLOCK_ID] => 2 [NAME] => DOI [ACTIVE] => Y [SORT] => 500 [CODE] => DOI [DEFAULT_VALUE] => [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 80 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 28 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => [USER_TYPE_SETTINGS] => [HINT] => [PROPERTY_VALUE_ID] => 11510 [VALUE] => 10.3205/ctt-2008-en-000016.01 [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => 10.3205/ctt-2008-en-000016.01 [~DESCRIPTION] => [~NAME] => DOI [~DEFAULT_VALUE] => ) [AUTHOR_EN] => Array ( [ID] => 37 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Author [ACTIVE] => Y [SORT] => 500 [CODE] => AUTHOR_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 37 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 11593 [VALUE] => Array ( [TEXT] => <p class="Autor">Claudia Lange, Figen Cakiroglu, Andrej Spiess, Heike Cappallo-Obermann, Axel R. Zander</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Claudia Lange, Figen Cakiroglu, Andrej Spiess, Heike Cappallo-Obermann, Axel R. Zander

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 11594 [VALUE] => Array ( [TEXT] => <p class="bodytext">Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany<br /><br /> <b>Correspondence:</b><br> Claudia Lange, Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany, <br>E-mail: <a href="javascript:linkTo_UnCryptMailto('qempxs.gpperkiDyoi2yrm1leqfyvk2hi');">cllange@<span style="display:none;">spam is bad</span>uke.uni-hamburg.de</a> </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

Correspondence:
Claudia Lange, Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany,
E-mail: cllange@spam is baduke.uni-hamburg.de

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Human bone marrow mesenchymal stromal cells (hMSC) are promising candidates for new treatment options in transplant and regenerative medicine. However, most expansion protocols still use fetal calf serum (FCS) as growth factor supplement, which is a potential source of undesirable xenogeneic pathogens. We established an easy and reproducible expansion protocol for hMSC based on the addition of platelet lysate (PL) obtained from human thrombocyte concentrates. Both CFU-F and cumulative cell numbers were significantly increased compared to the conventional FCS-based medium. The generated cells meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. Human MSC expanded with PL revealed favorable immunological properties in vitro. Gene expression profiles showed upregulation of cell cycle and DNA replication genes and downregulation of developmental, differentiation, adipogenic and MHC II genes. Thus, PL provides a safe component for accelerated and safe hMSC expansion.

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Platelet lysate for rapid expansion of human mesenchymal stromal cells

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Claudia Lange, Figen Cakiroglu, Andrej Spiess, Heike Cappallo-Obermann, Axel R. Zander

Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

Correspondence:
Claudia Lange, Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany,
E-mail: cllange@spam is baduke.uni-hamburg.de

Human bone marrow mesenchymal stromal cells (hMSC) are promising candidates for new treatment options in transplant and regenerative medicine. However, most expansion protocols still use fetal calf serum (FCS) as growth factor supplement, which is a potential source of undesirable xenogeneic pathogens. We established an easy and reproducible expansion protocol for hMSC based on the addition of platelet lysate (PL) obtained from human thrombocyte concentrates. Both CFU-F and cumulative cell numbers were significantly increased compared to the conventional FCS-based medium. The generated cells meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. Human MSC expanded with PL revealed favorable immunological properties in vitro. Gene expression profiles showed upregulation of cell cycle and DNA replication genes and downregulation of developmental, differentiation, adipogenic and MHC II genes. Thus, PL provides a safe component for accelerated and safe hMSC expansion.