ISSN 1866-8836
Клеточная терапия и трансплантация

Clinical safety and efficacy of mesenchymal stem cell transplantation for the treatment of heart diseases: A narrative review

Amir Nejad-Moghaddam1,2

1 Marine Medicine Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
2 Faculty of Science, Imam Khamenei University, Zibakenar, Rasht, Iran


Correspondence:
Dr. Amir Nejad-Moghaddam, Marine Medicine Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
Phone: +98 (911) 227-65-63
E-mail: mab.biology@gmail.com


Citation: Nejad-Moghaddam A. Clinical safety and efficacy of mesenchymal stem cell transplantation for the treatment of heart diseases: A narrative review. Cell Ther Transplant 2024; 13(1): 16-27.

doi 10.18620/ctt-1866-8836-2024-13-1-16-27
Submitted 20 December 2023
Accepted 01 March 2024

Summary

Stem cell therapy is a promising therapeutic approach for the treatment of heart diseases. One of the major challenges is identifying and selecting the best type of stem cell suitable for regenerative treatment. Bone marrow mononuclear cells, bone marrow, and adipose tissue-derived mesenchymal stem cells, endogenous cardiac stem cells, endothelial progenitor cells, and induced pluripotent stem cells are some of the types of stem cells that have been tested in order to promote the missed myocardial regeneration. Meanwhile, most of these cell types are evaluated for safety and efficacy in clinical trials. However, their clinical testing showed significant heterogeneity in terms of efficacy. Therefore, the main challenge is to provide clear experimental evidence of heart function improvement after stem cell administration. Among different transplant types, mesenchymal stem cells (MSCs) are derived from a wide range of sources and are easily isolated and cultured. MSCs have the capacity for proliferation and self-renewal in vitro, low immunogenicity and immunomodulatory properties, and, under certain conditions, may be differentiated into distinct cell types. In this review article, we take a comprehensive look at the use of MSCs for heart regeneration and discuss why related factors such as practicality and difficulty in cell collection should also be considered when selecting stem cells for transplantation.

Keywords

Cell therapy, regeneration, heart diseases, mesenchymal stem cell, cardiovascular disease, heart failure.


Introduction

According to the World Health Organization (WHO), cardiovascular disease (CVDs) is the leading cause of death in the world [1]. In 2021, about 20.5 million people died of cardiovascular disease, which accounts for 30% of all global deaths [2]. Of the 17 million premature deaths under the age of 70 caused by non-communicable diseases in 2019, 39% were due to cardiovascular disease [3]. Most cardiovascular diseases can be prevented by avoiding the behavioral risk factors such as smoking[4], unhealthy diet [5] and obesity [6], sedentary lifestyle [7] and harmful alcohol consumption [8]. It is important to diagnose cardiovascular disease as soon as possible so that it could be managed with counseling and medication.

Advanced cardiac support, medical treatment, and early reperfusion strategies have dramatically improved survival rate in patients with heart disease [9]. Despite this success, the risk of heart failure (HF) following myocardial infarction remains high in these patients, and there is no effective treatment to prevent this progression [10, 11]. Cardiac repair is strongly associated with the inflammatory process after injury, suggesting that targeting inflammation may be a promising way to preserving heart tissue and reducing mortality in patients surviving heart disease.

Stem cell therapies have the potential to fundamentally alter the conventional treatment of cardiovascular disease by stimulating damaged myocardial regeneration [12-14]. Over the past two decades, many clinical trials have demonstrated the safety and efficacy of multiple stem cell types. Various stem cell therapy studies have been performed by several groups for heart diseases, which can be divided into: (a) inhibition of remodeling after acute myocardial infarction; (b) stimulation of regeneration in chronically damaged hearts, and (c) induction of angiogenesis in coronary artery disease [15].

stem cell therapy studies have been performed by several groups for heart diseases, which can be divided into: (a) inhibition of remodeling after acute myocardial infarction; (b) stimulation of regeneration in chronically damaged hearts, and (c) induction of angiogenesis in coronary artery disease [15].

The aim of this review article was to investigate the usage of MSCs in regenerative medicine for the treatment of heart diseases. In addition, the potential mechanisms involved in stem cell-based heart repair are highlighted. Since the efficacy of stem cell therapy is quite limited, we will discuss more promising strategies to improve the transplantation outcomes.

Types of Stem Cells and their use in heart diseases treatment

Most of the available treatments can only act as rehabilitative approach to reduce the symptoms associated with the disease. Stem cell treatment can offer tremendous hope to the heart patients, especially in preventing the disease progression. Currently, stem cell therapy is the most preferred noninvasive treatment available. Various strategies have been applied by the medical science to limit the cardiac cells damage and reduce the symptoms with the help of stem cells.

Mesenchymal stem cells are unique primary cells in our body that are able to differentiate into distinct cell lineages [24]. This stem cell feature has been potentially used by many scientists for their clinical applications. Stem cells are inactive throughout a person's life, but may be adapted to specific tissue cells when needed for faster regeneration and repair [25]. Due to advanced technology, stem cells can now be isolated from two rich sources, i.e., bone marrow and adipose tissue [26]. Mesenchymal stem cells, when infused into the cardiac tissue, can differentiate into cardiac progenitor cells to restore lost heart function (Fig. 1).

Nejad-Moghaddam-fig01.jpg

Figure 1. Application of stem cells for treatment of heart diseases

Many clinical trials accrue from the use of MSCs for cardiovascular disease (CVD) treatment in animal model. Efficacy and safety of MSC in animal experiments is proven before starting clinical trials. There are several clinical trials underway which evaluate the safety and efficacy of MSCs in the treatment of heart diseases. In our review, we have considered 29 clinical trials which are terminated and ongoing on MSC types for treatment heart diseases.

In the new paradigm, autologous freshly isolated stromal vascular fraction (SVF) is reinjected into the patient without its expansion and differentiation in ex vivo culture, [27]. Umbilical cord (UC) blood is the most reliable and rich source of hematopoietic stem cells (HSCs). The Wharton’s jelly found in the umbilical cord tissue is a rich source of mesenchymal stem cells (MSCs). Using one’s own mesenchymal stem cells for treatment is a potentially a new treatment for cardiac diseases.

Therapeutic potential of mesenchymal stem cells for heart diseases

Mesenchymal stem cells (MSCs) are self-renewing, multipotent cells that can differentiate into many cell types, including osteocytes, chondrocytes, fat cells, hepatocytes, myocytes, neurons, and cardiomyocytes [28]. MSCs can be isolated from various tissues such as adipose tissue, bone marrow and umbilical cord. MSCs have a significant ability to modulate the immune response mainly by inhibiting T cell proliferation and protecting damaged tissues through paracrine mechanisms [29]. There is an urgent need to evaluate the true efficacy of the MSC transplant and its possible position in the current heart therapeutic.

Most early cell-based clinical trials for heart disease have been performed in cases of acute myocardial infarction (AMI) using autologous MSCs [30]. Extensive use of MSCs can be attributed to immediate cell access by the recipient. Isolation, ex vivo culture and manipulation of mature MSCs are easy to perform [31]. In this regard, MSCs, in part due to their long history in regenerative medicine, with proven safety and potency, are considered a major candidate cell type as confirmed by clinical research using this stem cell population in acute myocardial infarction (AMI) and chronic heart disease.

Myocardial infarction (MI) is the leading cause of death worldwide. The Global Burden of Disease Study reports that deaths from coronary heart disease in developing countries will double by 2030 [32]. Despite significant advances in treatment, ventricular dysfunction remains the leading cause of morbidity and mortality in these patients. Cell therapy is important for myocardial infarction. Intracoronary infusion of various cell populations (circulating progenitor cells, bone marrow-derived progenitor cells, bone marrow cells, peripheral blood stem cells, hematopoietic stem cells, and allogeneic bone marrow mesenchymal stromal cells) in acute MI has been used in some cases with promising results [33, 34]. There are several publications on the role of stem cell therapy in ischemic heart disease [35, 36].

Bone marrow-derived mesenchymal cell population (BM-MSCs) have both myogenic and angiogenic potential and have been studied for their therapeutic potential in regeneration/repair of damaged myocardial tissue. In addition, these cells are non-immunogenic [37] and have anti-inflammatory properties and facilitate vasculogenesis by increasing the level of vascular endothelial growth factor (VEGF) [38]. Clinical trials with MSCs for the treatment of heart diseases taken from clinical trials.gov website are listed in Table 1. The selection criteria of these trials included: distinct type of mesenchymal cell; numbers of injected cells, phase of the trial, and the effectiveness of the stem cell used.

Table 1. Mesenchymal stem cells therapy clinical trials for heart diseases

Nejad-Moghaddam-tab01-part01.jpg Nejad-Moghaddam-tab01-part02.jpg Nejad-Moghaddam-tab01-part03.jpg Nejad-Moghaddam-tab01-part04.jpg Nejad-Moghaddam-tab01-part05.jpg

Abbreviations: MSCs, Mesenchymal stem cells; MPCs, Mesenchymal precursor cells; UC-MSCs, Umbilical cord-derived mesenchymal stem cells; Ad-MSCs, Adipose tissue-derived mesenchymal stem cells; BM-MSCs, Bone marrow-derived mesenchymal stem cells, mBMC, mononuclear bone marrow cells; WJ-MSCs, Wharton's jelly-derived mesenchymal stem cells; MI, Myocardial Infarction; MI, Acute myocardial infarction; IHD, ischemic heart disease, CAD, coronary artery disease, ICM, Ischemic cardiomyopathy; DCM, dilated cardiomyopathy; HF, Heart failure; ILVD, Ischemic left ventricular dysfunction; LV, left heart ventricle.

Clinical trials for acute myocardial infarction, and ischemic coronary heart disease

Preliminary experimental and clinical studies suggest that transplantation of circulating blood-cells (CBC) or bone marrow-derived mesenchymal progenitor cell (BMPC) may beneficially affect post-infarction regeneration processes after acute MI. Yao and et al. observed 47 patients with ischemic heart disease which occurred after previous MI [73]. Of them, 24 were randomized to intracoronary infusion of BMPC (BMPC group), and 23 received an intracoronary saline infusion (control group). Left ventricle (LV) systolic and diastolic function, infarction size and myocardial perfusion deficiency were assessed by means of echocardiography, MRI or single-photon-emission computed tomography (SPECT) at baseline (before MI) and repeated at the 9 month of follow-up examination. BMPC treatment did not result in a significant increase in LV ejection fraction in either group by any of the diagnostic methods used, and the apparent tendency for improvement was not statistically different between the two groups. No inter-group changes were seen in diastolic and systolic end volume of LV, infarction size or myocardial perfusion rates. Autologous BMC transfusion in the patients with improved MI was associated with improved diastolic function [73].

Also, Britten et al. investigated functional effects of infused BMCs to quantitative outcomes at 4-month follow-up, performing serial contrast-enhanced MRI and assessing migratory capacity of the transplanted progenitor cells immediately after intracoronary infusion [74]. Analysis suggests that intracoronary infusion of BMCs in patients with AMI beneficially affects postinfarction remodeling processes.

Schaefer et al. showed that autologous BMCs transplantation improves LV ejection fraction in AMI patients. However, the effect of BMC therapy on diastolic LV function in patients after AMI remained unclear [75]. In this regard, autologous BMC intra-coronary transfusion has a limited therapeutic effect on echocardiographic parameters of diastolic function in patients after AMI. However, this effect is mainly related to the initial improvement of diastolic function parameters without a lasting effect at long-term follow-up [76]. Meyer et al. showed that intracoronary transfusion of autologous BM-MSCs may improve LV function in patients after AMI. However, clinical studies dealing with the effects of BM-MSCs after AMI have covered only limited time periods of 3 to 6 months [77].

Dill et al. reported that intracoronary administration of BM-MSCs improved LV function in patients with LV dysfunction after MI, despite reperfusion and optimal drug therapy at 1-year follow-up and beneficially with adverse LV remodeling [78]. Doppler subclinical study by Erbs et al, evaluate the effects of intra-coronary infusion of BM-MSCs on coronary blood flow regulation in patients with AMI[79]. The results showed that BM-MSCs treatment after AMI restored the microvascular function of infarcted arteries being associated with a significant improvement in maximal vascular flow capacity. These data provide clinical evidence for the concept that progenitor mesenchymal cell transplantation may contribute to repair of blood vessels [79].

Wöhrle et al. investigated the results of intracoronary mesenchymal stem cell therapy after AMI in 42 patients enrolled [80]. The patients received intracoronary infusion 380×106 mononuclear BMCs. The initial clinical parameters and cardiac magnetic resonance imaging (MRI) did not differ. No differences in secondary endpoints were observed between the two groups, including changes in infarction size or end-diastolic and end-systolic LV volume indexes. As a result, not found any evidence of a positive effect of intracoronary BMC on LV ejection fraction, LV volume indexes, or infarction size.

Tendera et al. studied the intracoronary infusion of BM-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute ST-elevation myocardial infarction (STEMI) and reduced left ventricular ejection fraction (LVEF) [81]. 200 patients were randomized to intracoronary infusion of BM cells or to the control group without BM cell treatment. Treatment with BM cells in patients with impaired AMI and LVEF did not cause significant improvement LVEF or volume. However, there was a trend toward better outcomes after cell therapy in patients with the most severe LVEF disorder and the longer delay between symptoms and revascularization.

Prognosis of progenitor cell transplantation and enhanced regeneration in AMI demonstrates both safety, feasibility, and potential effects on circulatory performance parameters of intracoronary myocardial infusion of circulating progenitor cells (CPCs) or bone marrow-derived progenitor cells (BMCs) in patients with AMI [82]. Intracoronary infusion of progenitor cells (either BMCs or CPC) is safe and feasible in patients after successful vascular reconstruction in AMI with stent implantation. Both excellent safety profile and the observed positive effects on LV regeneration make sense for larger double-blind randomized trials [82].

Intramyocardial cell injection

Intramyocardial BM cells injection is associated with improvements in myocardial blood flow and angina symptoms in patients with refractory angina. The effect of repeated injections of BM-MSCs into the heart muscle in patients with recurrent ischemia or myocardial ischemia has been studied previously [83]. In the study by Mann et al., 23 patients have shown an improved myocardial perfusion after the first injection but had residual or recurrent angina and ischemia on myocardial perfusion imaging by SPECT visualization. The patients again received intramyocardial injection of 1×108 autologous BM-MSCs, 2 years after the first injection[83]. Repeated BM cells injections in previously responding patients with refractory angina were associated with improvements in myocardial perfusion, anginal complaints, and quality of life score after 12 months of follow-up.

Rodrigo et al. reported that intramyocardial injection of BM-MSCs in chronic myocardial ischemia patients after previous placebo injection improves myocardial perfusion and anginal symptoms[84]. Sixteen patients, who previously received intramyocardial placebo injections within a randomized trial, 1×108 BMC were injected using the NOGA-system. Cardiovascular angina score and quality of life were evaluated at baseline, 3 and 6 months. LV end-systolic volume significantly decreased after BMC injection but not after placebo injection. LV end-diastolic volume and LV ejection fraction did not change. Intramyocardial BMC injection in patients with chronic myocardial ischemia significantly improved angina symptoms and myocardial perfusion. These results confirm the outcome of our previously reported randomized trial [84].

Mathiasen et al. assessed 4-year outcomes of intramyocardial injections of autologous BM-MSCs in 60 patients with ischemic heart failure [85]. Hospitalization for angina attacks was significantly lower in the MSC group, otherwise there was no difference in hospitalization or survival. No side effects were revealed. Intra-myocardial injection of autologous BM-MSCs improved heart function and myocardial mass in patients with ischemic heart failure. Randomized, double-blind, placebo-controlled trial at a Netherlands University hospital (trialregister.nl Identifier: NTR400 and isrctn.org Identifier: ISRCTN58194927), with 6-month follow-up was performed for intramyocardial 1×108 autologous BM-MSCs injection for chronic myocardial ischemia of 50 patients with chronic myocardial ischemia [86]. Injection of intramyocardial BM cells resulted in a statistically significant but moderate improvement in myocardial perfusion compared with placebo.

Beeres et al. investigated usefulness of intramyocardial injection of 1×108 autologous BM-MSCs in 20 patients with severe angina pectoris and stress-induced myocardial ischemia [87]. The results showed that injection of autologous BM-MSCs was safe in patients with ischemia, reduced angina symptoms, improved myocardial perfusion, and increased LV function.

In a study by Sørensen et al. patients with stable CAD and refractory angina were treated by direct injection of autologous MSCs into the myocardium, and the safety and efficacy of the treatment were monitored for 12 months [88]. A total of 31 patients were included with stable CAD, with moderate to severe angina, normal LV ejection fraction, and no further revascularization options. Seattle Angina Questionnaire (SAQ) evaluations demonstrated highly significant improvements in physical limitation, angina stability, angina frequency, and quality of life. autologous culture expanded MSCs is safe in the intermediate/long term to treat patients with stable CAD.

Conclusion

Stem cell therapy is a promising treatment strategy for patients with heart failure, accounting for more than 10% of deaths worldwide each year [12]. Despite more than a decade of research, further investigation is needed to determine whether stem cell regeneration therapy is an effective treatment strategy and can be routinely performed in clinical practice.

MSCs have many benefits, including available resources, easy separation, cell expansion and low immunogenicity. In addition, transplanted MSCs can migrate to myocardial infarcted tissue, reduce the inflammatory response, alleviate fibrosis, enhance the formation of new blood vessels, differentiate into cardiomyocyte-like cells and finally help repair myocardial infarction. Despite their benefits in treating heart disease, the use of MSCs still faces challenges such as poor targeted migration and low MSCs survival rates in the ischemic myocardium. The feasibility and safety of MSC treatment have been tested in many clinical trials, but the optimal dose of MSC and delivery route for treatment should be studied. However, some problems remain with using MSCs to treat heart disorders, MSCs are still a promising form of cell therapy.

Conflict of interest

The author confirms that there are no conflicts of interest.

Acknowledgements

This review article was supported by Marine Medicine Research Center, Baqiyatallah University of Medical Sciences.

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Volume 13, Number 1
03/31/2024

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doi 10.18620/ctt-1866-8836-2024-13-1-16-27
Submitted 20 December 2023
Accepted 01 March 2024

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