|Year : 2016 | Volume
| Issue : 4 | Page : 101-111
Mesenchymal stem cells for heart repair
Kan Wang, Qiyuan Xu
Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
|Date of Submission||12-Aug-2016|
|Date of Acceptance||28-Nov-2016|
|Date of Web Publication||3-Jan-2017|
Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou 310009
Source of Support: None, Conflict of Interest: None
With the aging of the population, ischemic heart disease including myocardial infarction, ischemic cardiomyopathy, and consequent heart failure became a leading cause of morbidity and mortality despite substantial advances in risk factor prevention, medicaments, and revascularization. Cell therapy is currently being investigated as a potential low-cost and low-risk alternative. Favorable results from preclinical studies have brought cardiac cell therapy into clinical trials. It has been demonstrated that mesenchymal stem cell (MSC)-based therapy is promising for tissue engineering and therapeutic applications due to their pluripotent differentiation and relative ease of obtain. This review focused on the utilization of MSC in cardiac repair and current status in clinical application.
Keywords: Cell therapy, heart repair, mesenchymal stem cells
|How to cite this article:|
Wang K, Xu Q. Mesenchymal stem cells for heart repair. Transl Surg 2016;1:101-11
| Introduction|| |
Heart diseases including myocardial infarction (MI) and ischemia are associated with the irreversible injury of cardiomyocytes and vasculature. However, the native capacity of the renewal and repair of myocardial tissue is currently inadequate as therapeutic measures to prevent left ventricular remodeling and heart failure. Stem cell transplantation has emerged as a potentially viable therapeutic approach to regenerate and repair the damaged myocardial tissue. ,,,,,,
Mesenchymal stem cells (MSCs) are pluripotent, self-renewing cells and can differentiate into osteoblasts, chondrocytes, adipocytes, , and also can be induced to differentiate in vitro into cardiomyocytes. ,, Since Orlic et al.  transplanted autologous MSC into infarcted mouse heart and observed cardiomyogenic (CMG) differentiation of these cells in 2001, numerous laboratory and clinical research studies involving cell transplantation for MI have been reported. Recent progress in tissue engineering and regenerative medicine has highlighted MSC as a potential source of cells, which are less immunogenic than other cell lines. , Besides transdifferentiation into cardiomyocytes, the therapeutic effects of MSC on myocardial repair may be due to multiple other aspects, including production of various paracrine cytokines and growth factors promoting angiogenesis and spontaneous cell fusion, attenuating apoptosis, and initiation of endogenous repair mechanisms. ,,,,,,,
In this review, we summarize the current literature on MSC-based therapy for myocardial injury from the standpoints of therapeutic efficacy, underlining mechanism, and application limitation to the formation of an optimized program. Indeed, with the advantage of low immunogenicity and few ethical debates, MSC therapy still has promising application prospects for treatment of ischemic heart diseases.
| Mesenchymal Stem Cell Application On Ischemic Diseases|| |
Although modern medical technology has greatly developed, ischemic injury and heart failure are still the primary reasons for human morbidity and disability all over the world. Since cardiomyocytes have poor regeneration ability, persistent cardiac ischemia and necrosis lead to a gradual loss of myocytes, ventricular remodeling, and chronic heart failure. This is the main reason for hospital admissions among the elderly.
The limited proliferation and self-renewal cannot compensate for heart injury, leading to replacement of cardiomyocytes by fibroblasts and consequent formation of fibrosis. Due to scar- and ischemia-related postinfarction events, clinical manifestations are significant and varied. The damaged ventricle undergoes progressive remodeling and chamber dilation. Medications, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG) are utilized in treating patients with ischemia cardiomyopathy (ICM), but none has benefit in functional cardiomyogenesis and scar reduction. Few effective intrinsic mechanisms affect myocardial repair and regeneration. Therefore, due to their great differentiation capacity, exogenous delivery of multipotent stem cells offers another feasible approach to accomplish myocardial regeneration and cardiac function recovery.
Among the various types of stem cells, cellular, molecular, and preclinical data have shown MSC to be suitable cell candidates for regenerative therapy after myocardial. Under proper conditions, MSC can be induced to differentiate into myocytes, endothelium, and smooth muscle cells (SMCs) in the infarcted heart,  revealing a powerful potential for cardiogenic differentiation MSC can be isolated from various sources, including bone marrow, adipose tissue, endometrial tissue, and especially umbilical cord blood, with its high ex vivo expansion capacity. ,,, Another important property of MSC is their powerful paracrine potential, which has been proved in many studies. The promising therapeutic effect of MSC also relies on their capacity to engraft and their long-term survival in distinctive target tissues.
The first report from Makino et al.  in 1999 demonstrated that bone marrow stem cells could improve cardiac function in infarcted animal heart and indicated that MSC might be a suitable candidate for MI repair. To confirm this hypothesis, Wang et al. , in China have spent several years focusing on the therapeutic effects and safety of bone marrow-derived MSC (BM-MSC) transplantation in animal models and in patients suffering from MI or chronic heart failure. They established MI animal models in New Zealand rabbits Sprague-Dawley (SD) rats, , and C57/B6 mice , by ligation of the left anterior descending artery. Allogeneic BM-MSCs were isolated, expanded in vitro, after identification, the cell suspension was injected intramyocardially into the myocardium at the border of infarcted region. Functional and histological parameters, including cardiac function, neovascularization formation, and infarct area size, were evaluated between the MSC engrafted hearts and the controls. Compared with the controls, MSC transplantation significantly increased left ventricle ejection fraction (LVEF), fraction shortening (FS), density of micro vessel, and decrease in the size of infarct zone. The therapeutic effects could also be achieved by heterogeneous MSC transplantation. ,, Moreover, they also reported solid beneficial efficacy of hypoxia-preconditioned MSC in infarcted monkey hearts, providing further confirmation in big animal models. 
For cardiomyopathy and chronic heart failure, animal studies have also been carried out to ascertain the therapeutic effects. Li et al. , had established dilated cardiomyopathy (DCM) models in rabbit hearts induced by intravenous injection of doxorubicin hydrochloride. Three weeks later, BM-MSC expansion was injected into the anterior wall of the left ventricle at four sites. Significantly increased cardiac function was observed in rabbits with allogeneic MSC injection compared with those of controls. Wang showed that a consistent improvement could be seen in DCM rabbits from umbilical cord blood derived-MSC transplantation.  Nagaya et al.  also showed that MSC injection into left ventricle of DCM rats could improve LVEF by attenuating fibrosis. Furthermore, a successful clinical report from Brehm and Strauer showed that a diabetes mellitus patient complicated by extensive acute MI (AMI) could benefit from autologous BM-MSC transplantation.  The engrafted cells successfully rescued the injured myocardium and reconstructed blood vessels, preserving cardiac contractile function. Wang et al. , established diabetes-related DCM models in SD rats by a bolus intraperitoneal injection of streptozotocin. Two weeks after, intramyocardially injection of rat BM-MSC, especially anoxic preconditioned MSC significantly increased FS. Anoxic preconditioned MSC increased the capillary density of diabetic myocardium and reduced collagen deposition of diabetic heart to attenuate myocardial fibrosis. In summary, all these data prove that MSC are adaptable candidates for DCM patients with chronic heart failure.
These results have encouraged scientists to perform further more investigations on MSC-based therapy. In recent decades, the amount of clinical trials relating to cell transplantation have been conducted around the world. [Table 1] presents some noted clinical trials on cell therapy to treat patients with AMI and ICM. The amount of positive results indicate that cell transplantation is useful for acute and sub-AMI patients, and with a limited improvement of cardiac function in patients with old MI and DCM, it also offers a promising hope for patients afflicted with these heart diseases. For instance, a meta-analysis of seven randomized, placebo-controlled clinical trials by Ge et al.  showed that transcoronary injection of autologous bone marrow-derived stem cells can dramatically improve postinfarcted LVEF and attenuate left ventricular end-systolic volume but does not alleviate left ventricular remodeling. Evidence from a series of clinical trials indicated that BM-MSC transplantation is a safe procedure and appears to be effective in patients with ICM. ,,
|Table 1: Comparison of clinical trials on bone marrow stem cells transplantation |
Click here to view
Compared with embryonic stem cells, cord blood-derived stem cell, and skeletal myoblast, MSC has a series of advantages, such as large volume, ease in acquisition, no ethical disputes, strong paracrine effects, poor immunogenicity, low tumorigenicity, and enhanced safety in clinical application. Although the mechanisms are still unclear, in the field of regenerative medicine, cell therapy is still a promising method of heart function restoration requiring further investigation.
In summary, BM-MSCs are ideal candidates of cardiac celloplasty for infarcted myocardium and chronic heart failure incurable with other treatments.
| Mechanisms Underlying The Bone Marrow-Derived Mesenchymal Stem Cell-Based Therapy|| |
MSCs are a group of nonhematopoietic multipotent stem cells in mesenchymal tissue, capable of differentiating into multiple mesoderm-type cells, such as osteoblasts, chondrocytes, adipocytes, and fibroblasts, as well as ectoderm-type cells, e.g., neuron-like cells , and endoderm-like cells, e.g., hepatocytes  under certain culture conditions in vitro. The differentiation characteristics of MSC have been illustrated by a number of experimental studies. Furthermore, numerous studies have been undertaken over the years to investigate the potential for BM-MSC to differentiate into functional cardiomyocytes both in vivo and in vitro.
In 1995, Wakitani et al.  first cultured rat BM-MSCs with 5-azacytidine and observed multinucleated myotubes after 7-11 days. Then, cells were stained with Sudan black-positive droplets in their cytoplasm, providing the evidence that MSC in the bone marrow of postnatal organisms may possess differentiation potential for myoprogenitor cells, which could be used in clinically relevant myogenic regeneration.
Subsequent studies continued, and data published by Fukuda and Hakuno , confirmed that BM-MSC could differentiate into cardiomyocytes in vitro when induced by 5-azacytidine. Their findings indicate that CMG cells expressed a1A-, a1B-, and a1D-adrenergic receptor before differentiation and expressed b1-, b2-adrenergic and M1-, M2-muscarinic receptors after they obtained the cardiomyocyte phenotype. These receptors, which are parts of functional signal transduction pathways, could modulate cell function.
Animal studies also suggested that MSCs could differentiate into cardiomyocytes and improve cardiac function, which attracted the attention of investigators, ,,,, although most studies manifested that differentiation is extremely rare under physiological conditions. In 2011, Mu et al.  found that BM-MSC could differentiate into cardiomyocyte-like cells induced by 5-azacytidine in a rabbit DCM model and could obviously alleviate DCM. Then, Xing et al.  found that combination of angiotensin II and 5-azacytidine could stimulate cardiomyocyte differentiation of MSC.
MSC can also differentiate into endothelial cells and SMCs under some specific microenvironment. ,,, Angiogenesis is one of the putative mechanisms in recovery of cardiac function after MSC transplantation, which may reduce the infarction size and promote repair processes. However, it also appears to be a rare event. 
The mechanisms responsible for the cardiovascular differentiation of MSC in infarcted heart are unclear. The traditional theory insisted that MSC transplantation into injured heart could improve cardiac function by inducing cardiomyogenesis. Many results of basic research using transplantation of MSC in postinfarct animal models demonstrated improved left ventricular function and reduction in infarction size, ,,,,,, resulting in a decrease in mortality.  These clinical cardiac improvements were obvious, but only limited numbers of cells undergoing cardiomyocyte differentiation were observed. ,,, In addition, Toma et al. investigated the myogenic differentiation potential of human MSC from adult bone marrow after transplanted into the adult murine myocardium. Only a small ratio of implanted cells survived at 7 days after transplantation and their morphologies resembled the surrounding host cardiomyocytes. By immunohistochemistry, they revealed de novo expressions of desmin, beta-myosin heavy chain, alpha-actinin, cardiac troponin T, and phospholamban in BM-MSC comparable to those in the host cardiomyocytes. The sarcomeric organization of the contractile proteins was observed in BM-MSC. Wang's team showed that injected MSCs were localized in the injection sites and transdifferentiated into cardiomyocyte-like cells, endothelial cells, and SMCs, reducing the infarcted extension and improving cardiac contractility by the survived myocytes. ,,, In the DCM rabbit models, the engrafted MSCs were found to proliferate and transdifferentiate into cardiomyocyte-like cells and endothelial cells. , These data dedicated the engrafted BM-MSC in the myocardium appears to differentiate in situ into cardiomyocytes, strongly supporting the basis for using these adult stem cells for cellular cardiomyoplasty.
Besides cardiac differentiation capacity of MSC, paracrine potential is another crucial mechanism modulating their cardioprotection. In 2005, Gnecchi et al.  had reported that paracrine action of BM-MSC was remarkable for protection of ischemic heart. After that, more and more attention of scientists had been driven to paracrine potential of MSC. Deuse et al. found that hepatocyte growth factor (HGF) or vascular endothelial growth factor (VEGF) overexpressing MSC secreted more cardioprotective conditioned medium for infarcted rat heart and preserved more cardiomyocytes. Tang et al.  proved that stromal cell-derived factor-1 overexpressed BM-MSC displayed paracrine activation of HGF to improve cardiac remodeling in rat model of MI; meanwhile, Cho et al.  reported glycogen synthase kinase (GSK)-3b upregulation in BM-MSC stimulated paracrine factors including VEGF and decreased MI size and left ventricle remodeling. Wang et al. have accomplished some achievements in paracrine action in MSC-based therapy. Their results indicated that hypoxia-preconditioned BM-MSC could enhance secretion of pro-survival and pro-angiogenic factors including hypoxia inducible factor 1, angiopoietin-1, VEGF and its receptor, Flk-1, erythropoietin, Bcl-2, and Bcl-xL to improve infarcted heart function.  The anti-apoptotic effects of transplanted BM-MSC were associated with inactivation of voltage-dependent potassium channels.  Attenuated postinfarcted ventricular remodeling might be mediated by the expression of downregulating matrix metalloproteinases (MMP-2, MMP-9) and reducing fibrosis.  Their further study discovered that leptin signaling played important role in BM-MSC conferred by hypoxia preconditioning process.  Recently, they confirmed therapeutic properties of hypoxia-preconditioned BM-MSCs in the nonhuman primate (cynomolgus monkeys), and finally drew the conclusion that paracrine activity without remuscularization was responsible.  Moreover, they also put attention on age-related senescence of BM-MSC and found SIRT1 could ameliorate the aging of BM-MSC. The paracrine factors including Ang I and fibroblast growth factor (FGF) were much more highly secreted from SIRT1 overexpressed BM-MSC in rat infarcted heart. ,
In addition, Wang's team applied BM-MSC to diabetic cardiomyopathy animal models to investigate therapeutic efficacy. , Their results showed that anoxic preconditioned MSC increased the capillary density of diabetic myocardium and attenuated myocardial fibrosis mediated by increased the secretion activity of MMP-2 and inhibited transforming growth factor b1, respectively. Anoxic preconditioned MSC significantly elicited anti-apoptosis in DCM rats, possibly mediated by upregulation of Bcl-2/Bax ratio and the inhibition caspase-3 expression and activation. The results indicate that intramyocardial transplantation of MSC, especially anoxic preconditioning MSC, has protective effects on diabetic cardiomyopathy, possibly through an anti-apoptosis and attenuation of cardiac remodeling.
As the study of paracrine effect of BM-MSC went further, scientist found small vesicle-like structures named "exosomes" in conditioned medium from BM-MSC.  Then, they discovered that the exosome contained not only protein but also microRNAs (miRNAs), transferred from BM-MSC to target cells to realize paracrine regulation in MI. ,,
In summary, the mechanisms of therapeutic effects by BM-MSC transplantation might include transdifferentiation and paracrine action in animal ischemic heart. Due to the low ratio of differentiation and further exposure in paracrine action, more and more researchers have transferred their attention from cardiomyocyte differentiation to the paracrine potential of BM-MSC. With further studies, the underlying mechanism will gradually become more clear.
| Application Obstacles And Optimum Proposal|| |
Although BM-MSC-based therapy has the effects of anti-apoptosis and neovascularization to repair infarcted heart, and may be significantly superior than medicine, PCI and CABG, some problems still exist in clinical application.
It has been demonstrated that BM-MSC could transdifferentiate into cardiomyocyte-like cells, endothelium, and SMCs in the infarcted myocardium. ,,,, However, there are inconsistent reports that the transplanted cells would undergo cell fusion with the host cardiomyocytes rather than perform transdifferentiation, , which limited the therapeutic efficacy of BM-MSC.
Evidence showed that most of BM-MSC cannot survival in infarcted myocardium for a long time. In 2008, van der Bogt et al.  used firefly luciferase (Fluc)-green fluorescence protein (GFP)-labeled BM-MSC to measure the survival rate, and their data showed that at 4 days after implantation, the survival of BM-MSC remained at 50%, and the ratio decreased to <10% at 21 days posttransplantation. The results from Cao et al.  's work illustrated that the survival rate of BM-MSC in infarcted rat heart remained 25% at 6 days after cell transplantation whereas all BM-MSC die out at day 9. In Wang's work published in 2016, the survival ratio of BM-MSC transplanted in cynomolgus monkeys infarcted heart was close to zero at day 28 posttransplantation.  It is well known that ventricle remodeling is a long-term pathophysiologic processes; low survival rate of BM-MSC will raise a lot of doubt about the therapeutic efficacy, which may hinder clinical application of BM-MSC.
Other problems are the potential side effects of BM-MSC transplantation. Intramyocardial injection of BM-MSC could direct delivery of cells; however, it also increases the risk of arrhythmia. Although BM-MSC has low immunogenicity, and autotransplantation rarely cause immunological rejection, as engrafted cells, the possible of blocking cardiac electrophysiological conducting pathway still exists.  This clinical question needs to be answered.
Faced with problems in BM-MSC-based therapy, some solutions are possible: (1) Extremely low transdifferentiation of BM-MSC is an obvious defect for cell transplantation. In 2015, Ikhapoh et al.  discovered Ang II promote but interleukin-6 and tumor necrosis factor-a (TNF-a) inhibit VEGF-A-induced differentiation of BM-MSC into endothelial cells. These findings have important clinical significances for therapies intended to increase differentiation of BM-MSC following intervention. Wang et al.  found basic FGF (bFGF) also augmented vascular differentiation of BM-MSC after injected in a canine infarct model. Furthermore, Hafez et al.  observed that combination treatment of bFGF and hydrocortisone can drives MSC differentiation to cardiomyocytes with a marginally higher efficiency. (2) Survival rate of engrafted BM-MSC sharply declines in host heart after a short-term, which make therapeutic efficacy questionable. Survival improvement will become the urgent problem that needs to be solved. For decades, scientists tried more and more methods to increase survival capacity. In this field, Wang et al. have focused attention on hypoxia preconditioning. In 2008, Wang et al. found that hypoxia preconditioning enhances the capacities of BM-MSC to repair infarcted myocardium, reducing cell death and apoptosis of implanted BM-MSC, thus increasing therapeutic efficacy.  In 2014, their further work indicated that leptin signaling is an early and essential step regulating the survival of hypoxia preconditioned BM-MSC in mice infarct heart.  Besides hypoxia preconditioning, prolyl hydroxylase inhibition also is an effective and feasible strategy to strengthen cell survival of BM-MSC transplanted into the ischemic heart of rats.  (3) It had been demonstrated that an appropriate ratio of transplanted cells to host cardiomyocytes contributes to the elicitation of therapeutic effects.  When human MSCs in vitro are cocultured with neonatal cardiomyocytes at a ratio of 1:9 or 1:4, reentrant arrhythmias could be induced in 86% of the cultured system MSCs cocultured with neonatal cardiomyocytes at a ratio of 1:99 does not lead to the decrease of conduction velocity and reentrant arrhythmias. The number of transplanted MSCs is a crucial aspect to cardiac electrophysiological heterogeneity and arrhythmogeneity after transplantation. Transcoronary injection of small amount of MSCs several times to treat MI in swine models is a feasible and safe pathway, increasing transplantation efficiency.  It is consistent with the results from Wang's group that duplicate transplantation of MSCs brought a high increase in cardiac function than one-shot of cell injection. (4) To avoid uncontrollable factors of BM-MSC-based therapy, intensive studies on paracrine action of BM-MSC have gone further. Although cytokine and growth factors were detected from conditioned medium in many articles, exosomes could be a novel candidate to replace BM-MSC for MI treatment. Exosomes have a microvesicle structure with a diameter about 100 nm and were discovered early in 1981  but have become a research hotspot in the last decade. In 2012, exosomes derived from BM-MSC were concerned as a promoter of tumor growth,  and their role as a stimulator of angiogenesis in MI model were reported in 2014.  Subsequent results demonstrated that exosomes not only played cardioprotective role via delivery miRNAs to target cells and stimulated survival signaling pathways but also stimulated neovascularization and restrain the inflammation response, thus improving heart function after ischemic injury. All these results dedicated that exosome could be qualified for cardioprotection performance completely without BM-MSC in animal infarct model. (5) Wang et al. have for a long time focused on the optimal time points after MI for cell transplantation. Consistent with the results from Lim et al. that a 6% increase of cardiac function was achieved by BM-MSC transplantation at the early stage of AMI in swine models,  Wang's group found that 2 weeks after AMI was an optimal time point to upregulate the impaired cardiac function for BM-MSC transplantation in rat models,  which may due to that the 2-week time window inflammation was attenuated and fibrosis remained unformed. , Consequently, many more studies and clinical trials are needed to prove the therapeutic effects of bone marrow-derived stem cells.
The bottlenecks of therapeutic effects by MSC transplantation for heart injury might raise some difficulties and confusion about that, but these problems aroused much more research interests of scientists to find better solutions for basic research and clinical application. Meanwhile, the prospects of MSC therapy remain promising as great progress of stem cell research. Enhancement of therapeutic effect is a major issue in MSC-based therapy for MI. Early in 2008, Hahn et al.  found MSCs pretreated with cocktails of growth factors including FGF-2, insulin-like growth factor-1, and bone morphogenetic protein-2, exhibited cytoprotection on neighboring cardiomyocytes. Gap junctions were augmented and therapeutic efficacy was improved. Later, the result reported by Deuse et al.  indicated that HGF and VEGF overexpressed changed MSC to a valuable source for cytokine production and maximize beneficial protection of MSC-based therapy. Another study showed that knocking down pigment epithelium-derived factor in aged MSC could induce cellular protection similar to young MSC, demonstrating a novel genetic modification target for optimizing MSC treatment.  Moreover, overexpressing Notch1 in MSC is critical for therapeutic benefits through decreased infarct size and improved cardiac function.  GSK-3b also was discovered as regulator of paracrine factors including VEGFA, platelet factor 4, FGF1/2, TNF, and hairy/enhancer-of-split related with YRPW motif protein 1/2 (Hey1/2), which not only increases survival of MSCs but also induces cardiomyocyte differentiation and angiogenesis.  These data proved MSCs could be modulated as a more suitable and superior option for cell therapy.
| Discussion|| |
Experimental findings and clinical trials have enhanced our understanding of MSC biology greatly over the last decade. MSC-based therapy still holds great promise for cardiac preservation and repair due to their unique attributes of immune tolerance, multipotency, and availability in the adult. Many shortcomings of MSC have now been identified, including poor rates of engraftment and survival in vivo, deficient CMG potential and compromised reparative effect when autologous cells are derived from older, comorbid patients. However, numerous diverse strategies have rapidly emerged from basic scientific innovation that target each of these limitations Improvements of MSC-based therapy have been produced by several groups, encouraging optimization techniques invented and applied in the clinical realm, providing the future of MSC-based therapy for cardiac repair more bright and promising.
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Conflicts of interest
There are no conflicts of interest.
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