Published online Jul 26, 2014. doi: 10.4330/wjc.v6.i7.610
Revised: February 21, 2014
Accepted: May 14, 2014
Published online: July 26, 2014
Post-myocardial infarction (MI), the left ventricle (LV) undergoes a series of events collectively referred to as remodeling. As a result, damaged myocardium is replaced with fibrotic tissue consequently leading to contractile dysfunction and ultimately heart failure. LV remodeling post-MI includes inflammatory, fibrotic, and neovascularization responses that involve regulated cell recruitment and function. Stem cells (SCs) have been transplanted post-MI for treatment of LV remodeling and shown to improve LV function by reduction in scar tissue formation in humans and animal models of MI. The promising results obtained from the application of SCs post-MI have sparked a massive effort to identify the optimal SC for regeneration of cardiomyocytes and the paradigm for clinical applications. Although SC transplantations are generally associated with new tissue formation, SCs also secrete cytokines, chemokines and growth factors that robustly regulate cell behavior in a paracrine fashion during the remodeling process. In this review, the different types of SCs used for cardiomyogenesis, markers of differentiation, paracrine factor secretion, and strategies for cell recruitment and delivery are addressed.
Core tip: Stem cell (SC)-based therapies hold promise to improve damaged myocardium repair and regeneration and thereby restore normal tissue function post-MI. In addition to the potential of SCs to regenerate myocardium, intrinsic properties of SCs such as their ability to home to areas of tissue damage make them an attractive tool for drug delivery. SCs, specifically mesenchymal stem cells, secrete multiple factors that can act in an autocrine and paracrine manner to regulate cell activation, recruitment, and survival during myocardium repair and regeneration.
- Citation: Zamilpa R, Navarro MM, Flores I, Griffey S. Stem cell mechanisms during left ventricular remodeling post-myocardial infarction: Repair and regeneration. World J Cardiol 2014; 6(7): 610-620
- URL: https://www.wjgnet.com/1949-8462/full/v6/i7/610.htm
- DOI: https://dx.doi.org/10.4330/wjc.v6.i7.610
In the United States alone, it is estimated that a myocardial infarction (MI) occurs every 35 s and approximately 20% of patients that experience a first-MI develop heart failure (HF) within 5 years[1]. An MI is consensually defined as the death of cardiomyocytes after a prolonged period of ischemia causing a progressive decline in cardiac function that ultimately results in HF[2]. Although the mortality associated with acute MI continues to decline as a result of revascularization, the morbidity and mortality caused by HF is on the rise[3,4].
Current post-MI pharmacological therapies such as ACE inhibitors and beta-blockers improve cardiac repair and slow down the progression to HF. However, the growing interest in stem cell (SC) therapies which not only promote repair but also hold promise to regenerate damaged myocardium has sparked a tremendous effort aimed at the development of an effective paradigm for ventricular remodeling post-MI. The possibility that SC therapies can restore cardiac function post-MI and increased evidence that the heart contains resident SCs niches has also contributed to this growing interest[5-7].
Post-MI, the LV undergoes a remodeling process that results in the replacement of damaged myocardium with a collagen scar[8-10]. During the remodeling process, the normal elliptical shape of the LV (Figure 1A) changes to spherical (Figure 1B) as illustrated by the echocardiogram of the murine heart following MI induced by permanent ligation of the left anterior descending coronary artery. Along with the architectural and structural changes, LV contractile function declines[10].
The magnitude of LV contractile dysfunction is dependent on the extent of the infarct and the wound healing response that follows which includes cardiomyocyte death, inflammatory response, granulation tissue synthesis and granulation tissue maturation and remodeling. Historically, the use of stem cells has automatically been associated with direct replacement of dead cardiomyocytes; however, more recent research has indicated that stem cells possess intricate properties that can regulate other aspects of myocardium repair post-MI. In this review we will focus on the application of stem cells as a therapeutic tool for treatment of myocardial damage post-acute MI and discuss the role of stem cells during cardiac repair and regeneration.
SCs are sophisticated cells with multifunctional properties that can orchestrate the wound healing process post-MI leading to restoration of normal tissue function (Figure 2). One of these properties is the ability to home to areas of injury which has led to the investigation of stem cells for targeted drug delivery[11-13]. Post-MI, SC transplantations have been shown to rescue apoptotic cardiomyocytes and give rise to mature cardiomyocytes through cell fusion[14,15]. In addition, multiple SC types have the capability of differentiating into functional cardiomyocytes which suggest that SCs can be used to replace necrotic or apoptotic cells post-MI. Further, SC transplantations have been shown to regulate the inflammatory response, reduce scarring, and promote angiogenesis through the paracrine effects, all of which lead to improved cardiac function in humans and animal models post-MI.
A major mechanism of action of SC transplantation post-MI that contributes to cardiac repair and regeneration is achieved through cell fusion. Using a combination of in vitro cell culture models and in vivo animal models of MI, fusion rates of SCs with injured cardiomyocytes were shown to significantly increase[14,15]. As a result, there was a decrease in cardiomyocyte apoptosis and an increase in the generation of mature cardiomyocytes[14-16]. Interestingly, inhibition of apoptosis was also achieved through paracrine effects using in vitro co-culture models through activation of the anti-apoptotic AKT/PKB pathway[15,16].
One of the primary goals of SC therapies post-MI is the replacement of dead cardiomyocytes. The current challenge in this regard is to identify the optimal SC for cardiomyocyte replacement. SCs are broadly classified based on their tissue of origin including embryonic vs adult, hematopoietic vs non-hematopoietic, and are further subcategorized by their differentiation potential. Stem cell differentiation potential is their ability to differentiate into specialized cells. By definition, a SC is not committed to one specific lineage and must therefore be given the appropriate differentiation signals if the paradigm calls for a cardiac progenitor or cardiomyocyte-differentiated cell. In Table 1, SCs that have been differentiated into a cardiogenic lineage and the methods of differentiation are listed.
| Cell type | Method of differentiation | Ref. |
| ESCs | EB-mediated differentiation | [17,18] |
| iPS | Transdifferentiation of iPS cell factor-based reprogrammed cardiac fibroblasts using EB-based method + transwell CM co-culture system | [19] |
| Direct reprogramming of cardiac fibroblasts in vivo by local delivery of GMT | [21] | |
| Suspension EB-mediated differentiation of reprogrammed adult fibroblasts | [22,23] | |
| Bone marrow MSC | In vitro differentiation induced by treatment with 5-azacytadine | [27,28] |
| In vivo differentiation of stem cells transplanted and mobilized to damaged myocardium | [29] | |
| In vivo differentiation of stem cells engrafted into the myocardium | [30] | |
| Differentiation using a cardiomyogenic differentiation medium containing insulin, DMSO, and ascorbic acid | [31] | |
| Adipose-derived MSC | Co-culture in direct contact with contracting cardiomyocytes | [37] |
| DMSO at 0.1% for 48 h | [38] | |
| Amniotic fluid SCs | In vivo differentiation of cells transplanted into myocardium | [33] |
| In vitro differentiation through EB formation | [35] | |
| Umbilical cord blood SCs | Co-culture with primary rat neonatal ventricular myocytes | [32] |
| Co-culture with mouse neonatal cardiomyocytes | [34] | |
| Wharton's Jelly MSCs | In vitro differentiation induced by treatment with 5-azacytadine or by culture in cardiomyocyte CM | [36] |
| CS | Co-culture with neonatal rat cardiomyocytes | [41] |
| CSP | Treatment with oxytocin or trichostatin A | [48] |
Embryonic stem cells (ESCs) have been differentiated into cardiomyocytes in vitro and in vivo. Expression of transcription factors GATA-4, myocyte-specific enhancer factors (MEF) 1 and 2C, and Nkx2.5 are commonly used for assessment of cardiomyocyte differentiation. Other factors such as atrial natriuretic factor, myosin light chain (MLC)-2v, myosin heavy chain (MHC), and phospholamban have also been used[16-18].
Human induced pluripotent stem (iPS) cells from various sources, including reprogrammed cardiac fibroblasts, have been differentiated into functional cardiomyocytes[19-23]. Early cardiac lineage differentiation markers include GATA-4, GATA6, Nkx2-5, the T-box 5 (Tbx5), insulin gene enhancer protein-1 (Isl1), and LIM homeodomain transcription factor[20].
To date, the most commonly used SCs for cardiac tissue regeneration have been derived from adult bone marrow. In 2001, Orlic et al[24] demonstrated that c-kit positive cells derived from bone marrow were able to generate de novo myocardium indicating that these cells might be ideal for treatment post-MI. Expansion of this study has demonstrated that bone marrow hematopoietic SCs give rise to cardiomyocytes through cell fusion rather than differentiation. Expression of α-actin, cardiac troponin T, and connexin-43 has been used for cardiac lineage differentiation[25]. In addition to c-kit positive cells, the bone marrow contains fibroblast-like, mesenchymal stromal cells (MSCs) also known as mesenchymal stem cells[26,27]. Studies using bone marrow MSCs have demonstrated that transplanted MSCs mobilize from the bone marrow into the ischemic myocardium post-MI. Consequently, these cells differentiate into cardiomyocytes suggesting that these cells play important roles in repair and regeneration post-MI[27-29]. Expression of α-actin, cardiac titin, cardiac troponin T, desmin, MHC, MEF 2A and 2D, and phospholamban have been used as markers for MSC cardiomyocyte differentiation[27,30,31].
Human-derived adipose MSCs, amniotic fluid SCs, umbilical cord blood hematopoietic cells and MSCs, and Wharton’s Jelly MSCs have also been differentiated to cardiomyocytes. Expression of α-actin, cardiac troponin I, GATA4, MHC, N-cadherin, Nkx2.5, and Tbx5 have been used for cardiac lineage differentiation characterization[32-38].
Interestingly, cardiac tissue homeostasis and regenerative potential has been shown to involve resident cardiac SCs and progenitor cells which have been isolated and expanded from adult human and mouse heart tissue biopsies[39-41]. At least four different types of resident cardiac SCs have been isolated and shown to differentiate into cardiomyocytes[41-47]. Interestingly, three of the four types of resident cardiac SCs identified so far have the ability to form cardiospheres (CS)[41,47]. α-actin and MEF2C are expressed by cardiomyocyte progenitors and developing cardiomyocytes. In addition to cardiosphere-derived cells, cardiac side population cells isolated from neonatal rat hearts have also been differentiated into beating cardiomyocytes by treatment with oxytocin or trichostatin A. In vivo, cardiac side specific cells demonstrated a superb ability to home to injured heart and differentiate into cardiomyocytes. Expression of cardiac transcription factors GATA-4, Nkx2.5 and MEF 2C as well as contractile proteins MHC and MLC-2v have been used for SP cell cardiomyocyte differentiation[48].
In addition to the ability of SCs to potentially replace dead cardiomyocytes, SCs provide a rich source of cytokines and growth factors that can act in an autocrine, paracrine, or endocrine fashion to regulate cell behavior during the inflammatory reaction post-MI[49].
The inflammatory response that follows an MI is necessary and plays a crucial role in proper healing and ventricular remodeling. Post-MI, myocardial necrosis initiates an inflammatory response that includes a cascade of cytokines and chemokines followed by recruitment of neutrophils and macrophages[50,51]. As summarized by Frangogiannis et al[51], the inflammatory reaction clears the damaged myocardium of cellular and matrix debris and activates the reparative process[51]. A prolonged inflammatory reaction leads to adverse remodeling and ventricular dysfunction due to untimely resolution of the acute inflammatory response, increased cardiomyocyte loss and resultant negative downstream effects to extracellular matrix (ECM) metabolism and neovascularization[50].
The most commonly used SC for transplantations post-MI are bone marrow-derived MSCs. The paracrine effects of MSCs have received far more recognition than their ability to replace dead cardiomyocytes. One of the therapeutic goals post-MI is to minimize cardiomyocyte loss. Transplantation of bone marrow MSCs has been shown to reduce cardiomyocyte loss through activation of the cell survival gene Akt[52]. Further, other anti-apoptotic effects of MSCs are postulated to include inhibition of nuclear factor κβ (NF-κB) activity, reduced production of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) as well as increased expression of IL-10[53-55].
As part of their involvement in the inflammatory response post-MI, polymorphonuclear granulocytes (PMNs; neutrophils) leave the circulation, infiltrate into the injured myocardium, secrete proteolytic enzymes and reactive oxygen species, and clear cellular and ECM debris[56,57]. Increased production of IL-6 by MSC’s has been shown to prevent apoptosis by activated neutrophils thereby increasing the lifespan of neutrophils through STAT3 transcription factors[58-60]. In addition, the increased production of IL-6 regulates neutrophil activation by attenuation of the respiratory burst[59,60].
Macrophages in the injured myocardium undergo a biphasic activation that begins with a pro-inflammatory phase (also known as M1 or classically activated) that is followed by an overlapping anti-inflammatory phase (also known as M2 or alternatively activated)[61,62]. The macrophage polarization switch from M1 to M2 is a key event in myocardium repair[51,63]. MSC transplantations post-MI increase the number of M2 macrophages[64]. While the mechanism is still unclear, it is likely mediated through paracrine effects that include CCL2, galectin-1, interferon-γ, IL-1β, indoleamine-2,3-dioxygenase, IL-4, IL-6, IL-10, IL-13, prostaglandin-E2, TNF-α, NF-κB, nitric oxide, heme oxygenase-1, hepatocyte growth factor, transforming growth factor-b1, and Human Leukocyte Antigen-G5[53,64,65].
MSC paracrine factors have also been shown to suppress T cell, natural killer cell, and B cell proliferation and attenuate the maturation of dendritic cells through paracrine factors as listed in Table 2[60,66-68].
| Factor | Outcome | Ref. |
| ↑Akt | Reduction cardiomyocyte loss | [52] |
| ↓ NF-κβ | Anti-apoptotic effects | [53-55] |
| ↓ TNF-α | Anti-apoptotic effects | [53-55] |
| ↓ IL-6 | Anti-apoptotic effects | [53-55] |
| ↑ IL-10 | Anti-apoptotic effects | [53-55] |
| ↑ IL-6 | Prevention activated neutrophil apoptosis via Stat3; regulation of neutrophil activation | [56-60] |
| ↑ IL-10, ↑TNF-α, and ↑ IL-6 | Macrophage M2 polarization | [53,61-65] |
| ↓ Collagen I and III, ↓ TIMP-1 and ↓TGF-β | Reduction in fibrosis and scar size | [55,69-76] |
| ↑ VEGF | Promote angiogenesis; improved contractile function | [77-86] |
| ↑ IL-6 | DC maturation inhibition | [60,66-68] |
| ↑ IDO and ↑PGE2 | Reduced T cell activation | [60,66-68] |
| ↑ IDO and ↑PGE2 | Decreased NK proliferation | [60] |
| Factor to be identified | B-Cell arrest | [60] |
Post-MI, necrotic cardiomyocytes are replaced with a fibrous scar. The extent of damaged tissue degradation and subsequent production of a provisional ECM affects scar thickness which in turn influences contractility of the surrounding myocardium. An increased degradation of ECM results in wall thinning and the development of aneurysms and LV rupture while an increased production of ECM results in fibrosis and can predispose the LV to HF[69]. Interestingly, SC transplantations post-MI have been shown to regulate scar formation post-MI and improve ventricular function.
Transplantation of beating cardiomyocytes produced in vitro from ESCs has been shown to attenuate scar thinning and increase fractional shortening post-MI[70]. iPS cell therapy in the mouse permanent ligation model has also been shown to reduce wall thinning post-MI[71]. Additionally, MSC transplantations have been shown to reduce fibrosis and scar size[55,72-74]. Studies by Xu and colleagues demonstrated that MSC transplantations in rats post-MI regulate LV remodeling by decreasing mRNA expression and protein levels of TGF-β, type I and type III collagens, and tissue inhibitor of metalloproteinase (TIMP)-1[75]. Interestingly, in sheep, MSC progenitor cell-injections into the border zone altered collagen dynamics in a cell concentration-dependent manner as a result of spatial changes in matrix metalloproteinases (MMPs) and TIMPs. MMPs -1, - 2, -3, -7, -9, -13, MT1-MMP, and TIMPs -1, -2, -4 were differentially altered in the remote, border zone, and infarct zones post-injection[76].
Angiogenesis is essential for myocardium repair and scar formation post-MI, and paracrine factors released following SC transplantations promote angiogenesis[77,78]. MSCs that engraft after transplantation post MI have been shown to express endothelial cell markers[79,80]. Consistent with these findings, MSCs have also been shown to secrete significantly elevated levels of vascular endothelial growth factor (VEGF). Concomitantly, capillary density increases in the infarct region contributing to improved regional and contractile function[81-83]. It is important to note that MSCs, preconditioned under hypoxic conditions, have an enhanced capacity to stimulate vascularization compared to MSCs cultured under normoxic conditions due to increased expression of VEGF, angiopoietin-1, and survival post-transplantation[84-86].
Several strategies have been used for SC therapeutic applications post-MI. These include cell infusion intravenously, intramyocardial injections, intracoronary applications, endocardial applications, and engineered delivery methods such as cardiac patches[87,88]. For SC recruitment, identification of chemoattractants that are responsible for SCs homing to damaged myocardium has shown an improvement in repair and ventricular function post-MI. Overexpression of stromal cell-derived factor-1 by transfected fibroblasts injected into the peri-infarct zone increased hematopoietic SC homing and improved fractional shortening in the rat MI model[89]. Monocyte chemotactic protein-3 also delivered in a similar fashion via transfected fibroblasts was shown to increase MSC engraftment. Although no significant regeneration of cardiomyocytes was observed, fractional shortening increased and LV end diastolic dimensions decreased[90]. In the porcine MI model, the combination of insulin growth factor-1 and hepatocyte growth factor activated endogenous cardiac SCs resulting in regeneration of cardiomyocytes and angiogenesis as well as improved cardiac function[91]. Interestingly, thymosin β4 has also been shown to play important roles in epicardial progenitor cell mobilization in the mouse heart for neovascularization[92,93].
For delivery, biological and synthetic scaffolds used as vehicles for SC transplantations have shown improvement in cell survival, engraftment and cardiomyogenesis. In the rat MI model, transplanted cardiac SCs using nano-topographical hydrogel patches that mimicked the native cardiac ECM improved cell integration, retention and myocardium regeneration[94]. Similarly, cardiac patches containing adipose stromal vascular cells increased coronary blood flow and significantly improved ejection fraction post-MI[95,96]. The combination of a hydrogel patch with encapsulation of MSCs, as designed by Levit and colleagues, improves cell survival and takes full advantage of MSC paracrine factors. In addition to significantly reduced scar size, delivery of encapsulated MSCs increased peri-infarct microvasculature and improved ejection fraction in the rat MI model[97].
Although numerous studies in humans and animal models have demonstrated that SC transplantations post-MI are safe and can improve cardiac healing and function, several common limitations associated with SC transplantations have been reported. The most common issues with SC transplantations for ventricular remodeling post-MI include reduced cell survival and engraftment which ultimately result in diminished cardiac regeneration and limited functional benefits. In human clinical trials, 3.2% of bone marrow SCs remained 24 h post-infusion, and in agreement with this outcome, other studies report less than 10% SC retention in human and animal studies[97-102]. Further, SCs that do engraft may differentiate into other lineages such as endothelial cells and fibroblasts rather than cardiomyocytes[103-105]. With regard to delivery methods, intravenous infusions may have decreased efficacy due to entrapment of cells in non-target tissues and organs such as bone marrow, lungs, liver and spleen[106,107]. Similarly, intracoronary and intramyocardial delivered cell retention is also limited and may reduce the efficacy of the transplanted cells due to the hostile milieu of the damaged heart[108,109]. Other reported issues with SC delivery methods include the potential for microembolism formation (intravenously and intracoronary), and the potential to induce arrhythmias (intracoronary and intramyocardial)[87,88].
The ultimate goal of SC applications is the translation of what has been learned in the laboratory to the production of safe and effective therapies for attenuation of adverse LV remodeling. In Table 3, the results from the most recently published clinical trials of SC therapies in treatment of myocardial damage post-acute MI are listed. In addition to the feasibility of cell delivery, the safety associated with SC transplantations continues to evolve in clinical trials. Conversely, common issues such as standardization of methodology (including cell dosing, cell product formulation, and timing of transplantation) and the innate heterogeneity of study populations which include other clinical factors such as advanced aging and diabetes hinder interpretation of trial outcomes resulting in the need for a larger-scale study[100-114]. On this front, it is very encouraging to see a significant increase in the number of clinical trials being performed across the globe. The Alliance for Regenerative Medicine annual report for 2012-2013 indicates there were 326 industry-sponsored cell therapy trials ongoing in early 2013. The report further indicates that the number of early to mid-stage cell therapy trials in cardiovascular-related diseases ranks second only to cell therapy studies involving cancer[115].
| Clinical trial | Outcome | Ref. | |
| 2010 | Influence of bone marrow stem cells on left ventricular perfusion and ejection fraction in patients with acute myocardial infarction of anterior wall: Randomized clinical trial | Slight improvement of myocardial profusion | [109] |
| 2011 | HEBE trial | No significant improvement on regional or global function | [110] |
| 2011 | Late TIME trial | No improvement on global or regional function at 6 mo | [111] |
| 2012 | Stem cell treatment for acute myocardial infarction | Reduced LVESV, LVEDV, and infarct size | [109] |
| 2012 | CADUCEUS trial | Reduced scar mass, increased myocardium viability, regional contractility and wall thickness | [112] |
| 2012 | Enhanced mobilization of the bone marrow-derived circulating progenitor cells by intracoronary freshly isolated bone marrow cells transplantation in patients with acute myocardial infarction | Feasibility, safety, and improvement on recovery of LV contractility | [113] |
| 2013 | The C-CURE trial | Feasibility, safety and improved LV ejection fraction | [114] |
A more specific review of acute MI clinical trials reveals that there were 36 open studies registered under “acute myocardial infarction and stem cells”. For congestive heart disease clinical trials the search revealed that there were 48 open studies registered under “congestive heart failure and stem cells” as of the writing of this review. Of these studies, there were 16 listed in phase 1 trials, 25 phase 2 trials, and 9 phase 3 trials (note that some studies are listed in overlapping phases). The majority of these studies are being conducted in the European Union and the United States with 15 and 12 registered studies, respectively[116].
The results from post-MI SC transplantations in animal models and humans have provided promising results in reducing scar formation and improved LV function which are achieved primarily through paracrine effects. While a great deal of information has been obtained in the past two decades on the roles SCs play in the post-MI setting, additional studies are needed to improve the efficacy of stem cell transplantations post-MI. Further, a consensus on the best time to initiate treatment, dosage, and delivery method is needed.
In summary, we have reviewed the current literature on the roles SCs play during LV remodeling post-MI. This evaluation includes different types of SCs with cardiomyogenic potential, markers of differentiation, trophic effects for the inflammatory, fibrotic and vascularization responses as well as strategies for cell homing and delivery post-MI.
The authors would like to thank Dr. Merry L. Lindsey for kindly providing the echocardiograms for the murine permanent ligation MI model.
P- Reviewer: Dominguez-Rodriguez A, Grignola JC, Gong KZ, Shah R S- Editor: Ji FF L- Editor: A E- Editor: Wu HL
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