The effect of plant extracts and plant-derived compounds on mesenchymal stromal cell differentiation

Introduction

Mesenchymal stromal cells (MSCs) are spindle shaped, adherent cells, resembling fibroblasts [1]. They can be isolated from several sources including peripheral blood, bone marrow, adipose tissue, tendon, skeleton muscle, trabecular bone and also from some neonatal tissues e.g. umbilical cord, umbilical cord blood and placenta [2]. The potential importance of MSCs in regenerative medicine, cell therapy and tissue engineering is indisputable [3]. They have been used in many clinical trials, including treatment of limb ischemia, Crohn’s disease, amyloidosis, ischemic stroke, respiratory distress syndrome, cardiac ischemia, diabetes, osteoarthritis, amyotrophic lateral sclerosis, multiple sclerosis, liver cirrhosis, graft-versus-host disease and rheumatoid arthritis [4].

MSCs are able to regenerate and differentiate into mesodermal lineages, such as osteocytes, adipocytes or chondrocytes [1]. In addition, many in vitro and in vivo studies have reported the ability of MSC to differentiate into several other mesodermal (fibroblasts, macrophages, smooth muscle cells, myoblasts, pericytes, endotheliocytes, cardiomyocytes) and non-mesodermal (neuron-like cells, Schwann cells, hepatocytes, oligodendrocytes, astrocytes, Langerhans islets cells) cell types [5]. It is well known that the differentiation of MSC is regulated by many external and internal factors [6]. It depends mainly on the optimal selection of differentiation-inducing factors such as cytokines, growth factors and serum supplements, and their precise concentration in the culture medium [7]. Today scientists treat MSCs lines with numerous herbal extracts and plant compounds to investigate their mechanistic effect on differentiation [8]. However, the above-described effect has been established for a limited number of phytochemicals only [9]. In this article we provide an analysis of the published literature on the utilization of plant extracts or plant-derived compounds in inducing MSCs differentiation, and a review of the potential mechanisms and pathways involved.

We based our analysis on the data collected from online databases e.g. Google Scholar and PubMed, using the keywords ‘mesenchymal stem/stromal cells’, ‘plant extracts’, ‘plant derived compounds’, ‘MSC differentiation’, ‘osteogenic differentiation’, 'chondrogenic differentiation’, ‘adipogenic differentiation’, ‘cardiogenic differentiation’, ‘neurogenic differentiation’.

Medicinal plants affecting MSC differentiation, and their variety

Due to their inherent beneficial properties herbs have traditionally been used as a major source of medicine in the treatment of many diseases [10]. Plant compounds combined with MSCs have also shown promising results in the treatment of different degenerative disorders of soft tissue and osteoporosis [11]. A number of synthetic and semi-synthetic products, such as growth factors and recombinant cytokines, are used nowadays as differentiation inducers in MSC research, but they have certain disadvantages – high cost and detectable side effects and toxicity. This is why researchers are looking for natural products which might be potentially active in MSC therapy [8]. The utilization of plant extracts to stimulate the differentiation of MSCs into desired lineage-progenitors may open up new horizons in regenerative medicine [4]. The ability of natural plant extracts (Table 1) and plant-derived compounds (Table 2) to promote differentiation of various MSCs has been shown in many studies.

In some instances, plant extracts have the ability to regulate transcription mechanisms [12] and activate many functions in cells and tissues at molecular level [13].

However, plant extracts may still show adverse effects in some unknown medical conditions. Better understanding of such effects may help us to restrict the undesirable utilization of the plant extracts in certain cases, adjust therapeutic doses, achieve the desired effect and control toxicity [4].

The specific effects of the distinct substances extracted from plants after in vitro MSC differentiation are summarized in Table 2.

Table 1. Some plant extracts that affect in vitro differentiation of mesenchymal stromal cells

Sources of mesenchymal cells: WJMSC, human Wharton's jelly; hBMSCs: human bone marrow; hDPMSCs, human dental pulp; muMSCs, murine C3H10T1/2 mesenchymal cells; hADMSCs: human adipose tissue; hABMSCs, human alveolar bone marrow; hUC-MSCs, human umbilical cord blood; mefMSCs, mouse embryonic fibroblasts; hGMSCs, human gingival tissue; hMeMSCs, human menstrual blood; pBMSCs, porcine bone marrow. Other abbreviations: ALP, alkaline phosphatase; OPG, osteoprotegerin; BSP, bone sialoprotein; OC, osteocalcin; cTnI, troponin; SOX9, SRY-box9; COLII, collagen type II; COLX, collagen type X; ACAN, aggrecan.

Table 2. Some of the plant-derived compounds that affect mesenchymal stromal cell differentiation

MSC sources:(see Table 1): hBMSCs: human bone marrow MSCs; hAMSCs: human amniotic mesenchymal stem cells, muMSCs, murine MSCs; mBMSCs, murine bone marrow MSCs. Other abbreviations: ALP, alkaline phosphatase; Runx2: runt-related transcription factor 2; BMP-2, human bone morphogenetic protein 2; OPN, osteopontin; OCN, osteocalcin; MYHC, myosin heavy chain.

MSC differentiation

Differentiation of MSCs into specific cell types starts with a molecular process called "commitment". In the body, cells need to receive cellular signals to differentiate, but in the condition of in vitro growth they cannot get chemical signals from other cells. Hence, the in vitro testing of MSC differentiation requires setting up controlled culture conditions, e.g. a mixture of biological factors that include different chemicals and recombinant proteins depending on the intended type of cells to be obtained [2]. MSC differentiation is a complex process which involves several signaling pathways (SWs). Other important modulators include transcription factors, e.g. peroxisome proliferator-activated receptor-gamma (PPAR-c) in adipogenesis and runt-related transcription factor 2 (RUNX2) in osteogenesis. There is also evidence that of the essential role of epigenetic mechanisms in the differentiation of MSCs [77].

Osteogenic differentiation pathway

Given the essential role of osteogenic differentiation of MSCs in maintaining bone homeostasis, promotion of this process becomes increasingly relevant for many scientists [3]. The molecular differentiation of MSCs into bone and cartilage is modulated by transforming growth factor-β/bone morphogenetic protein and Wnt signaling [78].

Osteogenic differentiation of MSCs is regulated by specific protein factors, e.g., bone morphogenetic protein 2 (BMP2), distal-less homeobox 5 (Dlx5) and runt-related transcription factor 2 (RUNX2), which commit MSCs to the osteogenic lineage. Upon further cultivation, MSCs can differentiate into preosteoblasts. RUNX2, β-catenin, and Osterix (Osx) induce the differentiation of preosteoblasts into immature osteoblasts. Osteoblasts differentiate later into mature osteoblasts which express P2X5, alkaline phosphatase, collagen type I and osteocalcin [2]. However, in certain pathophysiological conditions, the osteoblasts differentiation potential of MSCs may be decreased. Therefore, new strategies are required to increase osteogenic potential, which may be useful in cell-based bone regeneration therapy [79].

Previous studies have shown that many medicinal plants and plant-derived compounds can induce osteogenic differentiation of MSCs with several pathways involved. E.g., some flavonoids can play a certain role in the osteogenic differentiation of MSCs by targeting several pathways such as ERK, Wnt/β-catenin and PI3K/Akt, and regulating ALP, Osx, Cbfa1, Runx2 and BMP-2 [79]. Scientists have discovered that Eurycomanone significantly affects the bone formation process by activating AKT/GSK-3β/β-catenin SW [51]. There is a suggestion that 3,5-dicaffeoyl-epiquinic acid enhances osteoblast differentiation by stimulating Wnt/BMP signaling [55]. Another study showed that polysaccharide from Astragalus promotes the differentiation of MSCs into osteogenic lineage by facilitating the expression of ANKFY1 through the inhibition of miR-760 [57].

Adipogenic differentiation

The process of adipose tissue differentiation proceeds via a series of sequential steps. Once the cells are restricted to certain differentiation pathway (commitment stage), they develop into adipoblasts, and lipid granules begin to appear, with their number and size gradually increasing as the stages of cell development change [80], the cells then differentiate into spindle-shaped preadipocytes, then into early adipocytes, and eventually into mature adipocytes, circular in shape [81].

Many phytochemicals have been reported to induce adipogenic differentiation of MSCs. However, the exact mechanism of action is yet to be discovered. Wnt signaling is essential for the differentiation of adipocytes both in vitro and in vivo [82].

JAK2/STAT3 pathway has also been reported to play a certain role in the early stages of adipogenesis by regulating C/EBP beta transcription [83]. Previous studies have shown that the increase in intracellular levels of ROS by NAD(P)H oxidase 4 mediates adipogenic differentiation through CREB in MSC [84]. In addition, the inhibition of Notch signaling can promote adipogenesis of MSCs, mediated by autophagy involving PTEN-PI3K/Akt/mTOR pathway [85].

On the other hand, previous studies have shown that several phytochemicals such as delphinidin, dracunculin, libanoridin, Tithonia diversifolia, Ipomoea batatas have an inhibitory effect on adipogenesis. Many anti-adipogenic drugs act through inhibition of PPAR mediated by MAPK signaling [75]. Hedgehog SW had an inhibitory effect on adipogenesis in murine cells, such as mouse adipose-derived stromal cells, calvaria MSCs lines, C3H10T1/2 and KS483 [82]. It is reported that Wnt/β-catenin signaling may inhibit the adipogenic differentiation and direct the cell towards osteoblasts rather than adipocytes [86].

Chondrogenic differentiation

Cartilage damage is one of the most severe chronic disorders and a major cause of pain and disability in elderly [10]. Many studies suggested that some plant extracts and natural products can be used for cartilage regeneration, and may be considered a new and promising treatment for osteoarthritis. Plant extracts and natural products can promote chondrogenic differentiation of MSCs, and increase the expression of chondrogenic specific markers, such as Arctium lappa, Acacia nilotica, Pomegranate Extract, Tomato (Solanum lycopersicum), the triterpene Betulin, anthocyanidins (Cyanidin and delphinidin) (Tables 1-2).

Chondrogenic differentiation of MSCs is regulated by the interaction of various growth factors, cytokines, and signaling molecules [87]. SRY-box transcription factor 9 is a transcription factor required for chondrogenic differentiation. Activation of this factor regulates its downstream proteins such as aggrecan, cartilage oligomeric matrix protein, and collagen II. Transforming growth factor β (TGF-β) is also important for chondrogenesis through the activation of SMAD [42].

TGF-β3 is known to increase ECM secretion during chondrogenesis. TGF-β3 signaling is initiated by the binding to its receptor, and activation of intracellular signaling mediators to promote MSC differentiation, inhibit osteoblast maturation and regulate CD expression [10]. Wnt signaling also plays an important role in chondrogenesis. Its activity with minimum level is necessary for chondrogenic differentiation of MSCs, mild activation is required, as overexpression causes harmful effects on chondrogenic differentiation [88].

Issues of neurogenic differentiation

Several studies have reported the ability of MSCs to differentiate into neuron-like cells. However, there are some challenges in the differentiation process, such as high cost and rapid in vitro degradation of growth factors [89], low resistance of nerve cells during the culture process [45], and a greater tendency of recombinant/synthetic growth factors to induce the development of cancer cells if used for a long time. These challenges limit the use of MSCs in neuroregenerative therapy. To overcome this, scientists looked for new natural sources of neural differentiation inducers, with minimal side effects, low toxicity and readily available [89]. Previous research has shown that many medicinal plants, such as Chromolaena odorata, Astragalus mongholicus, Mucuna gigantean and Ciwujia, can induce neural differentiation of MSCs (Table 1).

It has been reported that the neurogenic differentiation process involves several factors, e.g. hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), 3-isobutyl-1-methylxanthine and dibutyryl cyclic AMP, retinoic acid (RA) and bFGF, glutathione and the phosphatidylcholine-specific phospholipase C inhibitor D609. The signaling pathways involved in the process are Wnt/β-catenin, Sox and Notch [90]. Wnt/PCP pathway can promote neural differentiation of MSC [91].

Cardiogenic differentiation

Cardiovascular diseases (CVD) is the leading cause of death worldwide. CVD often occurs as a result of damage to functional cardiomyocytes. MSCs based therapies are novel strategies for myocardial regeneration, improving the cardiac function after myocardial infarction [92].

Many studies have shown that MSC have the ability to differentiate into cardiomyocytes, and some research suggested that plant extracts could promote Cardiogenic differentiation of MSCs, such as Rehmannia glutinosa, Geum urbanum.

Factors affecting the differentiation of MSCs into cardiomyocytes are yet to be established. Infarction-associated biological and physical factors following myocardial infarction induce commitment of MSCs to cardiomyocyte-like cells through TGF1β and BMP2 pathways. Growth factors, such as myocardin, insulin-like growth factor-1 and VEGF can influence and enhance the ability of MSCs to differentiate into cardiomyocytes [93]. Other studies have demonstrated that several regulators of MSCs, such as HGF, PDGF, Wnt, and Notch-1 SWs are involved in the cardiogenic differentiation [94]. Another study revealed that cardiogenic differentiation of MSCs occurs through the activation of extracellular signal related kinases [95]. It has also been reported that cardiac differentiation of MSCs is driven by transcription factors NKX2.5 and GATA4 nuclear translocation [96]. Eventually, it has been found that flavonoid quercetin, a p38MAPK inhibitor, could promote cardiogenic differentiation by inhibiting Wnt and non-Smad TGF-β pathways [97].

Endothelial Differentiation

Endothelial dysfunction is a principal feature of vascular disease [98]. Endothelial cells are necessary to restore vascularity of ischemic tissues. This is an important aspect in the treatment of peripheral vascular diseases. MSCs are also considered a promising source of endothelial cells that can create a vascular network. Some plant compounds have been proven to promote MSCs differentiation into endothelial cells, such as the monoterpene Carvacrol (Table 2).

Although the mechanisms responsible for angiogenesis and vasculogenesis are still not fully understood, the available evidence strongly supports the important role of VEGF in both processes [99]. MSCs can induce angiogenesis by providing angiogenic factors such as VEGF and basic fibroblast growth factor [25].

Conclusion

The current review highlights the role of medicinal plants in inducing the differentiation of MSC. Further studies are needed to understand the pathways involved in the mechanism of action, identify the most effective phytochemicals and determine the optimum concentrations that must be used in vitro and in vivo research, which may have the utmost importance in cellular therapy and regenerative medicine.

Conflict of interest

The authors declare no conflict of interest.

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