Inflammation in myocardial injury: mesenchymal stem cells as potential immunomodulators

Abstract

Ischemic heart disease is a growing worldwide epidemic. Improvements in medical and surgical therapies have reduced early mortality after acute myocardial infarction and increased the number of patients living with chronic heart failure. The irreversible loss of functional cardiomyocytes puts these patients at significant risk of ongoing morbidity and mortality after their index event. Recent evidence suggests that inflammation is a key mediator of postinfarction adverse remodeling in the heart. In this review, we discuss the cardioprotective and deleterious effects of inflammation and its mediators during acute myocardial infarction. We also explore the role of mesenchymal stem cell therapy to limit secondary injury and promote myocardial healing after myocardial infarction.

INTRODUCTION

Ischemic heart disease is the number one cause of death worldwide accounting for over nine million deaths annually (117). Atherosclerotic plaque formation in epicardial coronary arteries leads to progressively diminished myocardial blood flow and ultimately results in myocardial injury or infarction (MI) through plaque rupture or critical supply-demand mismatch (174). Inflammation has long been known to play a vital role in both the progression of atherosclerosis, as well as secondary injury after myocardial damage (113, 122). Despite its foundational role in wound healing, an overwhelming inflammatory response after MI can have significant deleterious effects on cardiomyocytes and lead to worse patient outcomes (15). Improved understanding in the interactions between cells, extracellular matrix (ECM), and signaling molecules within the injured myocardium have allowed development of novel experimental therapies. These therapies seek to target the intricate balance between proinflammatory and anti-inflammatory pathways in an attempt to limit ischemic injury and prevent subsequent development of heart failure (34, 107, 154). Mesenchymal stem cells (MSCs), in particular, have emerged as potent paracrine modulators of inflammation that promote myocardial healing after infarction (68, 108, 138). The goals of this review are to discuss the cardioprotective and deleterious effects of inflammation and its individual mediators during acute MI and explore the immunomodulatory role of MSC therapy to limit secondary damage after MI.

INFLAMMATION FACILITATES HEALING AFTER ACUTE MYOCARDIAL INFARCTION

Myocardial injury and infarction is associated with an inflammatory cascade that is essential for debris removal and scar formation (58, 120). In an ST-elevation myocardial infarction (STEMI), sudden and complete coronary artery occlusion creates an acutely hypoxic environment known as an ischemic zone (80). Onset of cell death begins within 30 min to an hour after cessation of blood flow through a combination of necrosis and apoptosis (178). Necrosis in MI involves disruption of mitochondrial membranes driven by calcium transport dysregulation, secondary to anaerobic acidosis, while apoptosis can occur through both the intrinsic and extrinsic pathways (32, 129). The large amounts of cellular debris released by infarcted myocardium trigger a vigorous inflammatory response (Fig. 1).

Fig. 1.

Overview of inflammatory contributors after acute myocardial infarction. Acute occlusion of epicardial coronary arteries leads to massive cell death within hours of plaque rupture. This triggers multiple signaling pathway activations through innate immune system mechanisms, release of reactive oxygen species (ROS), and systemic neurohormonal signaling. These pathways ultimately result in the release of proinflammatory cytokines and recruitment of cellular mediators of inflammation, such as neutrophils and monocytes. These mediators are critical for sustaining an inflammatory response and eventual healing of the infarcted myocardium.

Complement Activation Initiates the Postinfarction Inflammatory Cascade

The release of cytosolic cellular constituents results in complement activation within 2 h of an acute MI (13, 141, 180, 195). The presence of mitochondrial membrane components, such as cardiolipin, outside the cell activate the classical complement pathway by directly binding complement component 1q (C1q) (149). This results in activation of the C1 complex (C1qC1rC1s), which cleaves both C4 and C2. C4b and C2a make up C3 convertase, which cleaves C3 to make C5 convertase (C4bC2aC3b), which subsequently cleaves C5 to facilitate chemotactic recruitment of neutrophils and monocytes (47, 75). Classical monocytes (Ly-6C^hi in mouse, CD14⁺⁺CD16^– in humans), in particular, are activated by the complement pathway and propagate the initial inflammatory cascade through secretion of large quantities of proinflammatory cytokines, including interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) (51, 116, 128, 153). Infiltrating neutrophils augment this response by supporting further recruitment and activation of classical monocytes (60, 164).

Reactive Oxygen Species Augment Inflammatory Signaling after Myocardial Infarction

Timely early reperfusion therapy is the standard of care for patients presenting with STEMI and reestablishes nutritive blood flow to reversibly injured myocardium (77, 130). Numerous epidemiologic studies over the past two decades have shown reduced morbidity and mortality with early percutaneous coronary intervention (PCI) for acutely occluded coronary arteries (172). However, the ischemia-reperfusion process can also increase the generation of reactive oxygen species (ROS) within the affected myocardium upon reestablishment of blood flow (14, 168). Cardiomyocytes contain large numbers of mitochondria that can potentially generate ROS through the electron transport chain. In physiological conditions, 2% of oxygen consumed is converted to highly reactive superoxide, which is rapidly reduced by intrinsic antioxidant mechanisms (186). During acute ischemia, however, there is a backlog of electrons in the electron transport chain due to the lack of its final electron acceptor that results in leakage of electrons from the mitochondria (30). These electrons react with residual oxygen molecules to form supraphysiological quantities of superoxide. Simultaneously, ischemia depletes cellular ADP in favor of ATP and AMP through the action of adenylate kinase. Upon reperfusion, the combination of increased oxygen availability and lack of available ADP further increases electron leakage and ultimately results in generation of additional ROS (30, 97).

ROS have been implicated in causing a wide range of deleterious effects in the myocardium (42, 99, 191). During acute MI, exposure of cardiac fibroblasts and infiltrating neutrophils to excess ROS results in the activation of ASK1 mitogen-activated protein (MAP) kinase kinase kinase and p38 MAP kinase within these cells (29, 37, 76). These pathways lead to downstream activation of the master transcription factor nuclear factor-κB (NF-κB) and directs production of TNF-α (76, 196). Additionally, ROS triggers cardiac mast cell degranulation in the perivascular space to release large amounts of TNF-α and histamines (57, 93). TNF-α induces further ROS production through mitochondrial uncoupling and amplifies NF-κB activation (73). TNF-α also influences production of other proinflammatory cytokines, such as IL-1β and IL-6, to help sustain the inflammatory response after MI (31, 36, 62, 71, 88).

Danger Signals Facilitates Innate Immune Response to Myocardial Infarction

Necrotic cells within infarcting myocardium release specific molecules, known as damage-associated molecular patterns (DAMPs), into the extracellular matrix and bloodstream that serve as danger signals to activate the host innate immune system (119). These ligands consist of various nucleic acids, ECM components, and intracellular proteins that are recognized by a family of evolutionarily conserved pattern recognition receptors known as Toll-like receptors (TLRs) (89). Major DAMPs released after MI include heat shock proteins (HSPs) 60 and 70, high mobility group box 1 protein (HMGB1), ECM fragments (consisting of hyaluronic acid and fibronectin), mitochondrial DNA (mtDNA), and messenger RNA (mRNA). HSPs, HMGB1 and ECM fragments are recognized by circulating TLR2 and TLR4,while mtDNA and mRNA are recognized by TLR9 and TLR3, respectively (40, 131, 169). Activation of TLRs result in recruitment of the adaptor protein myeloid-differentiation primary response protein 88 (MyD88), which facilitates a proinflammatory response through activation of NF-κB (1, 9). Furthermore, danger signals, such as IL-1α released by necrotic cardiomyocytes have also been shown to directly activate MyD88 in cardiac fibroblasts, independent of TLR signaling (109). This results in the release of proinflammatory cytokines, including TNF-α and IL-1β, which facilitate recruitment and activation of myeloid cells within the infarct site (33, 183, 193).

Neutrophils and Monocytes are Recruited to Acutely Infarcted Myocardium

The first cellular mediators of inflammation to arrive in the infarcted myocardium are neutrophils. NF-κB activation and release of complement pathway fragment C5a after myocardial infarction result in the synthesis of various CCL and CXCL family chemokines (56). CXCL family chemokines, in particular CXCL8, have been shown facilitate recruitment of neutrophils to the infarcted myocardium (24). As the prototypic neutrophil chemotactic factor, CXCL8 binds the CXCR1 and CXCR2 surface receptors to recruit neutrophils along its chemotactic gradient (8). Simultaneously, endothelial activation results in upregulation of key leukocyte adhesion molecules, including ICAM-1, P-selectin, and E-selectin (135). Neutrophil L-selectin recognizes these adhesion molecules and facilitates neutrophil rolling and transmigration through junctional adhesion molecule family proteins at the infarct site (189, 190). This process guides the characteristic pattern of neutrophil infiltration seen 6 to 8 h after an acute MI.

Despite the large numbers of neutrophils recruited, they do not appear to be the primary inflammatory mediator of post-MI repair. Recent evidence suggests that monocytes serve as central participants in this process, and neutrophils play an important role in facilitating their recruitment (23). Proinflammatory classical monocytes are recruited early after MI by CCL family chemokines CCL2 and CCL7 in a CCR2-dependent fashion (41). Once recruited, these monocytes propagate the inflammatory response through ongoing production of IL-1β and TNF-α and give rise to proinflammatory M1 macrophages, which clear cellular debris and damaged ECM through phagocytosis and proteolysis (51, 152).

Neurohormonal Signaling Sustains Monocyte Response after Myocardial Infarction

Monocytes are produced in steady state from bone marrow hematopoietic progenitor cells in response to macrophage colony-stimulating factor. More than half of the body’s undifferentiated monocytes are stored in reserve within the subcapsular red pulp of the spleen and released in response to acute myocardial injury (181). While CCL2 and CCL7 signaling is sufficient for recruitment of circulating and bone marrow monocytes, splenic monocyte mobilization appears to depend on the combination of CCR2 and ANG II signaling (101, 170, 184). Circulating ANG II levels are increased after MI through activation of the renin-angiotensin-aldosterone system. This occurs as a result of both direct renin release from peri-infarct zones of the myocardium, as well as secondary signaling from a sudden decrease in myocardial contractility and cardiac output (38, 49). This, in part, facilitates the release of splenic classical proinflammatory monocytes, which are rapidly recruited to infarcted myocardium (102).

Splenic monocyte reserves are rapidly depleted after acute MI, and ongoing monocyte production is maintained, in part, through sympathoadrenergic signaling. Myocardial ischemia increases myocardial interstitial and serum catecholamine levels through both local reflex sympathetic release of norepinephrine and systemic release of epinephrine and norepinephrine, resulting in a net increase in vascular tone (96, 158). These catecholamines signal the bone marrow niche cells to release hematopoietic stem cells and progenitor cells into circulation and sustain monocyte production within the spleen (50). Classical proinflammatory monocytes are subsequently released into circulation to both maintain and augment the inflammatory response within the postinfarct myocardium (148).

Monocytes Facilitate Myocardial Healing and Fibrosis

Monocyte recruitment to the infarcted myocardium is biphasic, with classical proinflammatory monocytes being the predominant monocyte subset recruited within the first 48 h (125, 150). By 5 days postinfarction, however, nonclassical anti-inflammatory monocytes (Ly-6C^lo in mouse, CD14⁺CD16⁺⁺ in humans) and macrophages begin to dominate the peri-infarct regions (132). These cells arrive through both differentiation of classical monocytes into nonclassical macrophages and CX3CR1-dependent recruitment of circulating nonclassical monocytes (74). They are critical for the reparative stage following acute MI and secrete prohealing cytokines, including transforming growth factor-β (TGF-β), IL-10, and vascular endothelial growth factor (92, 132, 173). These factors facilitate the transdifferentiation of cardiac fibroblasts into α-smooth muscle actin-expressing myofibroblasts, degradation of damaged ECM, deposition of collagen for initiation of scar formation, and stabilization of the infarct through release of fibronectin (51). This remodeling helps to stiffen the myocardium and prevent potential rupture that may result from ongoing dilation (194).

Mediators of Inflammation May Be Cytoprotective after Myocardial Injury

Many studies have shown that both NF-κB and TNF-α signaling can have cardioprotective effects in the setting of acute MI. Activation of NF-κB occurs through the proteasomal degradation of its inhibitor, inhibitor of κBα (IκBα). IκB kinase (IKK) phosphorylates the signal response domain of IκBα in response to stimuli-driven signaling and leads to its ubiquitination (118). The β-subunit of IKK, IKKβ, has been shown to promote cardiomyocyte survival in hypoxic conditions through repression of the proapoptotic Bcl-2 family protein BNIP3 (11, 146, 159). Furthermore, in vivo studies have shown that TNF-α can have contradicting effects on the postinfarct myocardium through different signaling pathways: activation of TNF receptor 1 (TNFR1) appears to be cardiotoxic, while activation of TNF receptor 2 (TNFR2) appears to be cardioprotective (198). Finally, other innate immune mediators, such as TLR signaling, can also help maintain myocardial contractility and prevent cardiomyocyte apoptosis in the setting of acute MI (25, 35, 199).

PROLONGED INFLAMMATION IS DETRIMENTAL TO THE POSTINFARCT MYOCARDIUM

The acute loss of contractile myocardium associated with MI creates a change in ventricular loading conditions to promote ventricular dilatation, cardiomyocyte hypertrophy, and fibrosis (139, 167). However, research on the relationship between infarct size and left ventricular remodeling has identified a group of patients with adverse remodeling that seems out of proportion to their initial infarct size (157, 188). Instead, there is increasing evidence to suggest inflammation is not limited to the infarcted myocardium, and systemic imbalances in the postinfarct inflammatory cascade can exacerbate adverse remodeling beyond the infarct site (98, 126). Clinically, subsets of patients with higher degrees of inflammation, as measured by serum C-reactive protein levels, appeared to be at higher risk for mechanical complications, ventricular aneurysms, and mortality (6, 7).

A number of studies have examined the role of proinflammatory cytokines in adverse ventricular remodeling (133, 134, 137). TNF-α, in particular, has been shown to induce cardiomyocyte apoptosis and subsequent adverse ventricular remodeling in the infarcted heart (43, 44, 45, 86). Sustained TNF-α signaling depletes cytoprotective proteins for both the intrinsic and extrinsic apoptosis pathways within cardiomyocytes. Additionally, its interaction with cardiomyocyte TNFR1 can directly promote cell death through recruitment of TNFR1-associated DEATH domain protein (TRADD) and receptor-interacting serine/threonine-protein kinase 1 (RIP1) (72, 124). TRADD and RIP1 form complexes with TNF receptor-associated factor 2 and/or Fas-associated protein with death domain to, in turn, activate JNKs and inhibit cellular FLICE-inhibitory protein (c-FLIP) (3). JNK signaling promotes generalized proteolysis and caspase-independent cell death, while inhibition of c-FLIP activates caspase 8 to trigger caspase-dependent cell death (114). This ultimately results in further loss of cardiomyocytes with worsening ventricular loading conditions and, consequently, increased degrees of adverse remodeling (175).

TNF-α also has profound effects on ECM remodeling after MI. Collagen, as the chief constituent of myocardial ECM, provides structural support to cells in the cardiac microenvironment (52, 53). Postinfarct, TNF-α activates myocardial matrix metalloproteinases (MMPs) and dysregulates tissue inhibitors of MMPs to breakdown extracellular collagen (106, 162). This results in wall thinning with increased ventricular compliance and contributes to adverse ventricular remodelling after MI (18). Animal models of TNF-α inhibition have shown promise in reducing adverse ventricular remodeling through downregulation of MMP-9 and MMP-13 (17, 79). Further efforts are under way to modulate TNF-α and other proinflammatory signaling pathways in hopes of reducing morbidity and mortality after acute MI (136).

MESENCHYMAL STEM CELLS AND IMMUNOMODULATION FOR THE POSTINFARCT HEART

MSCs refer to a set of plastic-adherent multipotent stem cells located in adult tissues (e.g., bone marrow) that are self-renewing and can give rise to multiple mesoderm lineages. These cells are easy to isolate in large quantities, to culture in vitro, and have capacity to differentiate into adipocytes, osteoblasts, and chondrocytes (66). These unique properties have led to tremendous interest in their use for cardiac regeneration. Multiple animal and human studies have been conducted with the goal of using MSCs to replace cardiomyocytes lost during acute myocardial injury (161).

MSCs Differentiate into Cardiomyocytes In Vitro

The in vitro differentiation of MSCs into beating cardiomyocytes was first described by Makino et al. in 1999 (112). These early experiences used cytidine analogs such as 5-azacytidine (5-aza) to induce nonspecific DNA demethylation (20). Spontaneously beating cells were identified by direct observation and demonstrated cardiomyocyte-like structure, protein expression, and action potentials. These cells also express increased amounts of connexin 43 and have been shown in murine models to increase overall connexin 43 expression within infarcted myocardium (5, 103). Transplantation of these treated MSCs in a rat myocardial injury model also demonstrated reductions in scar area at 5 wk after transplantation (87, 176). However, safety concerns regarding the use of 5-aza have led to studies looking for alternative methods of differentiation MSCs into cardiomyocytes. Current efforts are under way to explore the use of microRNAs, growth factors, cytokines, and three-dimentional microenvironments to induce cardiomyocyte differentiation of MSCs (69).

Despite this enthusiasm, it was subsequently observed that MSCs implanted into infarct sites do not stably engraft and are rapidly lost from the myocardium (70, 78, 104). Furthermore, very little, if any, in vivo differentiation to cardiomyocytes has been observed in transplanted MSCs (100, 144). Nevertheless, multiple studies have shown that MSC therapy improves ventricular function, reduces adverse remodeling, and improves functional status in animals and patients after acute MI (28). This benefit appears to be secondary to the nonprogenitor functions of MSCs, namely, paracrine signaling and cell-cell interactions (22, 64, 82, 85, 140). These functions allow implanted MSCs to alter the host immune response and promote endogenous tissue healing after MI to drive improved patient outcomes (Fig. 2).

Fig. 2.

Mesenchymal stem cells (MSCs) exert paracrine effects on cellular mediators of inflammation. MSCs secrete large numbers paracrine signaling molecules that affect the maturation, proliferation, and activity of various cellular mediators of inflammation. When delivered after an acute myocardial infarction, these functions help to accelerate the transition from inflammation to infarct healing.

Benefits of MSC Therapy Do Not Rely on Myocardial Delivery

Although early MSC studies relied on intracoronary or intramyocardial injection, MSCs have also been delivered in animal studies and human trials through peripheral intravenous infusion. In support of their paracrine functions, the efficacy of MSC therapy does not depend on engraftment of cells to the myocardium (94, 108). Several studies have shown that despite lower infarct zone engraftment and higher pulmonary retention of MSCs with intravenous injection relative to intramyocardial implantation, improvements in left ventricular ejection fraction (LVEF) were seen with both (59). This further supports that MSC injection may affect the systemic inflammatory process that follows an acute MI rather than function directly as progenitor cells. Nevertheless, a meta-analysis published by Kanelidis et al. (84) showed that intramyocardial injection of MSCs through catheter-based transendocardial stem cell injection offered additional benefits over intravenous infusion, suggesting that their presence within the myocardium may offer additional benefits over their systemic immunomodulatory functions.

MSCs Are Activated by the Inflammatory Niche

Because of their low level expression of major histocompatibility complex (MHC) class I and nonexpression of MHC class II molecules, MSCs are generally considered to be immune evasive (4). They require an inflammatory niche to activate their immunomodulatory effects on lymphocyte activation, proliferation, and differentiation (91). In vivo, MSCs home preferentially to infarcted myocardium after acute MI and are subsequently activated within the postinfarct inflammatory environment (127, 143). High concentrations of proinflammatory cytokines, such as INF-γ, TNF-α, IL-1α, and IL-1β work synergistically to activate MSCs and polarize them toward immunosuppressive phenotypes (105, 147). Recent evidence also suggests that cell-mediated cytotoxicity toward MSCs may further induce their immunomodulatory properties (63). Efforts are currently being made to preactivate MSCs in vitro to optimize their in vivo effects after therapeutic infusion (26, 142).

MSCs Participate in Paracrine Signaling to Improve Outcomes after Myocardial Infarction

Paracrine signaling by MSCs is achieved through secretion of soluble factors, including TGF-β, hepatocyte growth factor (HGF), stromal cell-derived factor-1, nitric oxide, heme oxygenase-1, IL-6, PGE₂ and indoleamine 2,3-dioxygenase (IDO) (19, 65, 110, 177). These factors facilitate the immunomodulatory effects of MSCs by suppressing the recruitment, activation, and proliferation of proinflammatory lymphocytes and promoting production of immunomodulatory regulatory T cells. They also play a key role in polarizing macrophages toward the reparative M2 phenotype and inhibiting maturation of dendritic cells. Additionally, recent studies have shown that MSCs also secrete exosomes to influence immune cells and cardiomyocytes (90, 115). When introduced after a myocardial infarction, these MSC-secreted factors act synergistically to decrease proinflammatory activation, reduce cardiomyocyte apoptosis, and improve postinfarction angiogenesis within the infarcted tissue (185). A summary of the immunomodulatory effects of key MSC-secreted paracrine mediators is presented in Table 1.

Table 1.

Key immunomodulatory paracrine factors secreted by MSCs

Factor	Function	References
HGF	Induction of immunomodulatory monocytes and macrophages Suppression of proinflammatory CD4+ T cells	(27, 46, 61, 83, 151)
HO-1	Decreases production of proinflammatory cytokines	(171, 197)
IDO	Inhibits T-cell and NK-cell activation and proliferation Promotes M2 macrophage polarization	(55, 121, 166)
IL-6	Pleiotropic effects on immune cells Induces secretion of PGE2 Inhibits dendritic cell maturation Inhibits neutrophil and lymphocyte apoptosis	(16, 48, 145, 192)
NO	Inhibits T-cell proliferation	(54, 155)
PGE2	Enhances inhibitory function of regulatory T cells Inhibits NK-cell activation and proliferation Inhibits dendritic cell maturation Promotes M2 macrophage polarization	(12, 165, 166, 182)
SDF-1	Recruitment of M2 macrophages Recruitment of progenitor cells	(21, 179)
TGF-β	Decreases leukocyte adhesion and migration Reduces macrophage secretion of proinflammatory cytokines	(67, 163, 187)

HGF, hepatocyte growth factor; HO-1, heme oxygenase-1; IDO, indoleamine 2,3-dioxygenase; IL-6, interleukin-6; MSCs, mesenchymal stem cells; NO, nitric oxide; PGE₂, prostaglandin E₂; SDF-1, stromal cell-derived factor-1; TGF-β, transforming growth factor-β.

MSCs Affect Leukocyte Activation, Proliferation, and Maturation

In addition to their systemic secretory functions, transplanted MSCs have been shown to interact with both innate and adaptive immune system leukocytes to facilitate targeted immunosuppression (160). Their main actions in the innate immune system involve monocyte/macrophage trafficking and polarization. In one study, MSCs have been shown to reduce mobilization of classical proinflammatory monocytes from the spleen through reduction of ventricular CCL-2 expression during acute myocardial inflammation (123). Other studies have shown that MSC infusion after MI reduces the proportion of proinflammatory M1 macrophages within the infarcted myocardium and simultaneously drive polarization of monocytes toward the alternatively activated M2 state (39). This reduces the amount of proinflammatory cytokines (including TNF-α and IL-1β) within the infarcted myocardium. The presence of M2 macrophages further produces soluble factors, including TGF-β, IL-10, HGF, PGE₂, and IDO to suppress the proinflammatory state (111). Taken together, these findings suggest that MSC administration after MI can accelerate the transition from inflammation to infarct healing.

Activated MSCs have also been shown to suppress the adaptive immune system. They secrete high levels of chemokines to attract T cells, B cells, macrophages, and dendritic cells, and can influence them through contact-mediated signaling and locally secreted factors (147). Through a series of studies, MSCs have been shown to express Fas ligand (FasL) to directly trigger T-cell apoptosis via the Fas/FasL pathway, as well as facilitate inhibition of T-cell proliferation through the programmed death 1 pathway (2, 10). Though the role of adaptive immunity in MI is unclear, autoreactivity may play a role in progression of adverse remodeling and progression of heart failure (156). More detailed studies are required to understand the postinfarct interplay between the innate and adaptive immune systems.

MSC Therapy Show Benefits in Human Clinical Trials

One of the early randomized controlled trials of MSC therapy in humans was reported by Chen et al. in 2004 (28). They randomized 69 patients presenting with acute MI to receive PCI with or without intracoronary injection of autologous bone marrow MSCs. The MSCs were delivered at an average of 18 days after the initial PCI intervention, and patients who received MSCs had an average 14% improvement in LVEF at 6 mo (P < 0.01) relative to control patients. Smaller infarct sizes on PET perfusion imaging and decreased LV adverse remodeling by LV volume measurements on echocardiography were also observed. These promising findings have led to multitudes of other studies to assess the safety and efficacy of MSC therapy in humans.

The safety of MSC therapy for acute MI was specifically explored in a meta-analysis published by Lalu et al. (95) in 2018. By looking across 11 human MSC studies (with a total of 509 patients) for acute MI and 12 studies (with 639 patients) for ischemic heart failure, they summarized that there were no associations between MSC therapy and acute adverse events relative to the control groups. They did find an unexplained increased risk of delayed neurologic adverse events with MSC administration (odds ratio 3.79, P < 0.05), although they simultaneously noted limitations in the interpretation of this signal due to the lack of detailed adverse event reporting in original trials. Overall, MSC therapy significantly improved LVEF of patients included in this meta-analysis and especially within the acute MI subcohort. This suggests that MSC therapy may offer favorable risk-benefit profiles for the secondary treatment of acute myocardial infarction.

In a separate meta-analysis, Jeong et al. (81) explored the efficacy of MSC therapy in ischemic heart disease in 14 published randomized placebo-controlled trials encompassing 950 patients. They noted that MSC treatment improves LVEF by 3.84% (95% CI 2.32–5.35) relative to the control group with corresponding decreases in adverse remodeling reflected in reduced LV end-systolic volume and end-diastolic volumes. These benefits persisted out to 2 yr from time of MSC implantation. Furthermore, MSC therapy improved patient function with improved scores on the 6-min walk test at 6 mo. Nonsignificant trends were also seen in favor of MSC-treated patients for reduced mortality and heart failure rehospitalization. These findings echo other findings and suggest that MSC therapy is beneficial, although larger and more rigorous trials are needed to quantify its safety and efficacy (Fig. 3).

Fig. 3.

The role of mesenchymal stem cells for treatment of acute myocardial infarction. Intramyocardial or systemic intravenous delivery of mesenchymal stem cells after an acute myocardial infection can promote myocardial healing through multiple mechanisms. Early in vitro evidence has shown that MSCs may have some capacity to differentiate into cardiomyocytes and replenish cells lost with myocardial injury. Further evidence has shown that MSCs participate in paracrine signaling to prevent cardiomyocyte apoptosis, decrease recruitment of proinflammatory cells, and drive monocytes to take on an anti-inflammatory prohealing phenotype over the classical proinflammatory phenotype. These properties have resulted in MSCs offering promise of reduced left ventricular adverse remodeling and improved patient functional status in early human clinical trials.

Conclusion

The inflammatory reaction following an acute myocardial infarction is a “double-edged sword” that results in both beneficial and detrimental effects. The acute postinfarct inflammation is necessary to clear away debris and to initiate healing with scar formation. However, persistent immune activation can worsen myocardial damage and drive adverse cardiac remodeling. Immunomodulatory therapy with MSCs may hold promise as a treatment option. This novel therapy can help attenuate the severity of inflammation and polarize mediators of inflammation toward a reparative phenotype. Early clinical experiences have suggested both safety and efficacy with its use for ischemic heart disease. Further laboratory studies are necessary to understand the detailed cellular and molecular interplay between MSCs, cardiomyocytes, and the immune system after myocardial infarction, and larger clinical studies are needed to better characterize the full risk-benefit profile of its use as a viable therapeutic option.

DISCLOSURES

R. C. Arora has received an unrestricted educational grant from Pfizer Canada, Inc., and honoraria from Mallinckrodt Pharmaceuticals for work unrelated to this work. All authors declare that there are no conflicts of interest, financial or otherwise, related to this work.

AUTHOR CONTRIBUTIONS

W.Y., E.A.-ER., S.S., and S.D. conceived and designed research; W.Y. prepared figures; W.Y., E.A.-ER., S.S., and S.D. drafted manuscript; L.A.K., R.C.A., and S.D. edited and revised manuscript; and W.Y., E.A.-ER., S.S., L.A.K., R.C.A., and S.D. approved final version of manuscript.