Abstract
Stem cells possessing the potential to replace damaged myocardium with functional myocytes have drawn increasing attention in the past decade in treating ischemic heart diseases; these diseases are the leading cause of morbidity and mortality in the world. The adult heart has recently been shown to contain a few cardiac stem cells (CSCs) that, in theory, suggest cardiac repair following acute myocardial infarction is possible if the CSC titer could be increased. Stem cell-based therapies, including hematopoietic stem cells and mesenchymal stem cells, were proven to be marginal and transitional. Multiple factors and mechanisms, rather than direct cardiac regeneration are involved in stem cell-mediated cardiac functional improvement. This review will focus on (1) the interaction between inflammation and stem cells; (2) the fate of stem cells at the microcirculatory level, and their subsequent influences on stem cell-based therapies.
Keywords: Stem cell, Inflammation, Microcirculation, Ischemic heart disease, Cardiac repair, Cell-based therapy
Introduction
Acute myocardial infarction is the leading cause of morbidity and mortality in the world. Reperfusion is the only way to rescue the ischemic heart by restoration of blood flow and oxygen supply. Early restoration of blood supply in the ischemic myocardium restricts the infarction size and improves clinical outcomes [13]. However, reperfusion itself is typically accompanied by acute inflammation and pulses of oxidative stress, resulting in further tissue damage, and referred to as reperfusion injury [5, 80]. Stem cells have increasingly attracted the attention of the bench scientist and the clinician interested in treating ischemic heart disease, due to their potential for repairing damaged cardiac tissue. However, the improvement of cardiac function has been proven to be marginal and transitional in both preclinical and clinical studies. The actual regeneration of damaged cardiac tissue was minimal, and below the level needed to achieve clinical benefits. This review will focus on the influence of inflammation, a major factor implicated in reperfusion injury, and microcirculation, the primary site where reperfusion injury is initially manifested, to further explore how these factors affect stem cell-based therapies.
Inflammation and ischemia/reperfusion injury
Inflammation mediated ischemia/reperfusion (I/R) injury has been extensively studied. In the acute phase of reperfusion injury, neutrophils are one of the earliest responders and the major mechanism for acute reperfusion injury. Activation of neutrophils is triggered by a variety of factors induced by ischemia, such as complement fragment C5a, reactive oxygen species (ROS), and pro-inflammatory cytokines (e.g. TNF-alpha, IL-1 and IL-6). Upon reperfusion, all the vascular beds downstream of the infarct inevitably interact with the activated neutrophils. (1) Post-capillary venues are the classical location for neutrophil recruitment. Activated neutrophile upregulate the adhesion molecules and interact with endothelial cells via the well-known mechanism of rolling-adhesion-diapedesis [6]. Significant adhesion and emigration of neutrophils were observed as early as 1 h after the onset of reperfusion, starting from the border zone and extending deeper into the infarct by 3 h [26]. Myeloperoxidase and NADPH oxidase are the major contributors to the neutrophil oxidative burst, and cause direct injury to the endothelial cells and cardiomyocytes [18, 92]. (2) At the capillary level, activated neutrophils are trapped in the microvessels due to their increased stiffness and decreased deformability, which contributes to the no-flow phenomena observed in reperfusion that prolongs the ischemia period in the downstream tissue [19, 86]. (3) Increased neutrophil adhesion to the arterial endothelium, associated with impaired endothelium-dependent vasodilation, was also evidenced after reperfusion [92]. Moreover, both clinical study and basic research highlighted C-reactive protein as a critical pathophysiological factor in myocardial microembolization and impaired reperfusion [69], which will pose dentrimental effects on the migration, differentiation and survival of stem cells in the ischemic heart.
TNF-alpha is one of the important up-stream signals that initiate the cytokine cascade, and exerts ambivalent effect in the infarct or reperfused myocardium [34, 66]. Gao et al. revealed that TNF-alpha-induced coronary microvascular dysfunction following I/R was independent of neutrophils. In neutropenic mice or in mice treated with a neutrophil NAD(P)H oxidase inhibitor, I/R induced similar endothelial dysfunction when compared with the control group [22]. Our work suggested that TNF-alpha might be the initiator of coronary vascular dysfunction by two lines of evidence: (a) TNF-alpha expression was induced or up-regulated in coronary arteriole smooth muscle cells, macrophages and master cells, both at the mRNA and protein levels [22], (b) Pre-treatment with TNF-neutralizing antibody before I/R attenuated both endothelial dysfunction in coronary arterioles [22] and infarct size [39]. Using TNF-alpha over-expression mice (TNF++/++), TNF knockout mice (TNF−/−) and their heterozygous cross mice (TNF−/++), a direct relationship was demonstrated between levels of TNF-alpha expression and endothelial dysfunction in reperfusion injury [89]. In consistent, recent clinical data revealed that TNF-alpha may contribute to coronary dys-function by potentiating the effects of vaso-constrictors in vein graft bypassed patients [33].
Endogenous stem cells in ischemic heart diseases
Cardiomyocytes early on came to be considered terminally differentiated and to offer little to no hope for repopulation of damaged cardiac tissue by adjacent cardiomyocytes. Alternative efforts by dedicated cardiovascular scientists also have yet to find a satisfactory treatment for rescuing cardiac function after I/R injury. Despite skepticism regarding the regenerative capacity of the adult heart accumulating evidence has emerged to show that even the healthy adult heart keeps renewing itself. In the adult mouse heart, the proliferating cells comprised from 0.25 to 1% of the entire cardiac cell population [67]. However, the proliferation rate of cardiomyocytes, which represents 20% of the total cardiac cells, was only 0.0005% [70]. Anversa et al. [4] pointed out that the size of proliferating cells in the heart is much smaller than the mature cardiomyocytes, and suggested the renewal of caridomyocytes may be achieved by stem cells. The concept of cardiac stem cells is now widely accepted and the presence is in evidence [38, 43, 59]. However, due to their extremely low abundance in the heart (about one in 30,000–40,000 myocardial cells) [38], the role of cardiac stem cells in cardiac repair following acute myocardial infarction is doubtful. Furthermore, the markedly inability for differentiation of cardiac stem cells in the infarct area was also reported as compared to those in the viable myocardium [38].
In addition to cardiac stem cells, stem cells outside of the heart may also contribute to cardiac repair. In adults, bone marrow is the major source of stem cells. There are two major groups of stem cells, the hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). HSCs give rise to red blood cells, platelets, monocytes and lymphocytes, while MSCs are generally regarded as bone marrow driven non-HSCs that are able to adhere to the plastic culture dish in vitro. MSCs are easy to multiply in culture and readily differentiated into mesenchymal lineages, such as osteoblasts, chondrocytes and adipocytes [60]. There are two lines of evidence in support of the argument that external stem cells may migrate to the heart and differentiate into cardiomyocytes as well as other cardiac cells. (1) In vitro studies demonstrated that bone marrow derived cells have the potential to differentiate into cardiomyocytes [45]. (2) Sex-mismatched cardiac transplantation in humans confirmed the presence of host derived-cardiomyocytes in the transplanted heart [28, 36, 50, 62].
Following myocardial infarction, mobilization of both HSCs and MSCs from bone marrow has been reported [15, 25, 40, 47, 77, 85]. The mobilization of stem cells is usually defined as increased circulating stem cells bearing various cell surface markers, such as CD34, CXCR4, CD117 (also known as c-kit), c-met, CD133, etc. Although multiple disease status, physical exercises, and cytokines expression have been shown to correlate with increases in circulating stem cell numbers [53, 55, 78, 90], direct evidence for regeneration of infracted cardiomyocytes by bone marrow-derived stem cells is lacking. In fact, scar formation is the common fate of the infracted myocardium.
Stem cell-based therapies
Whereas the extremely low abundance of stem cells in our body may minimize their utility for cardiac self-regeneration, stem cell-based therapies attempt to promote cardiac repair by direct delivery of a large number of exogenous stem cells to the infarct area. In 2001, Orlic et al. [56] first reported that the injection of bone marrow-derived Lin− c-kit+ stem cells, a subset of HSCs, into the infracted heart drove cardiac regeneration by differentiation into cardiac cells, including cardiomyocytes, muscle cells and endothelial cells. However, these observations were seriously challenged by other groups based on very similar protocols [8, 51]. The diverse fates of the administrated HSCs were thought to be due to different tracking methods used by these authors [14]. We also noticed that these studies were based on very different animal strains. Orlic et al. [56] adopted C57BL/6 mice in their experiments, which is a widely used mouse strain and often regarded as a standard strain. The other two groups used MHC–nLAC and C57BL/Ka strains, respectively. The MHC–nLAC mouse is of DBA/2J background [70], which often contrasts with C57BL/6J and shows a low susceptibility to atherosclerosis. The C57BL/Ka mouse is reported as a model for the human idiopathic paraproteinaemia and multiple myeloma [63, 64]. These distinct animal strains may have significant influence on the actual population of HSCs and/or their ability for cardiac differentiation. The outcome of infarct healing in mice also strongly depends on genetic background [79]. Recently, a similar set of progenitor cells (c-kit+ CD45−) was identified in the adult human heart, containing potential of endothelial but not cardiac differentiation [68]. Wnt signaling, a key regulator of stem cell growth, differentiation, and proliferation, was suggested to be involved in resident Sc a progenitor cells and endothelial cells after myocardial infarction [54].
In addition to these original observations, a wide range of stem cells, such as embryonic stem cells, skeletal myoblasts, bone marrow mononuclear cells, endothelial progenitor cells, mesenchymal cells, etc., were reported to be beneficial to cardiac function following infarction, [48]. However, the overall benefits of stem cell-based therapies are marginal and transitional [83], which indicate that the regeneration of infract myocardium is not the predominant mechanism for stem cell-based therapy. Emerging evidence suggests multiple mechanisms could be involved, including paracrine, angiogenesis, cell fusion, and passive mechanical effects, and influence of endogenous cardiac stem cells [83]. Unfortunately, without substantial regeneration of new myocardium to replace the infarct tissue, scar formation and adverse remodeling in the left ventricle often lead to heart failure.
Fate of exogenous stem cells
Following implantation, the intravital engraftment and differentiation of stem cells into cardiomyocytes are not guarantied. In a healthy animal model, intra-artery or intravenous infusion of ex vivo expanded MSCs were trapped primarily in the lung and then secondarily in the liver and other organs. Pretreatment with sodium nitro-prusside (a vessel dilator) increased the lung clearance resulting in a larger proportion of infused cells detected in the liver [21]. In a rat model of myocardial infarction, Barbash et al. [9] found that the majority of the stem cells were trapped in the lung following systemic intravenous infusion. Less than 1% of the infused stem cells were detected in the injured heart. However, direct left ventricular cavity infusion improved stem cell engraftment to the ischemic myocardium. This evidence indicates the micro-vasculature might function as a physical barrier that blocks the trafficking of exogenous stem cells. Toma et al. further tested this hypothesis by tracking the fate of intra-artery infused ex vivo with expanded MSCs. The authors found that 92% of the infused stem cells were arrested in the pre-capillary level during the first pass, with a 27% reduction of blood flow in the feeding arterioles. As a result, only 14% of the stem cells survived the microembolization-induced ischemia by 72 h, and extravasated the mciro-vascular wall [7, 76]. Although the deformability of the ex vivo expanded MSCs were comparable to the white blood cells, the actual size of these cells are much bigger than normal white blood cells as well as the capillaries. Thus, intra-vascular delivery of stem cells might cause further ischemia in the targeted tissue and/or result in a loss of the majority of the infused cells [7, 76].
These concerns that infusion of ex vivo expanded stem cells may exacerbate myocardial infarction were confirmed in healthy animal studies. Intra-coronary infusion of MSCs into healthy dogs [81] or sheep [24] resulted in immediate elevation of the ST segment in electrocardiograms (a marker of regional myocardial ischemia) and histological evidence of myocardial infarction was shown 7 days later. The size of the ex vivo expanded MSCs was larger than the freshly isolated bone marrow cells and thought to be the main reason causing the microcirculatory obstruction [81]. The severity of the injury also occurred in a dose-dependent manner [24].
Direct intracardiac injection of stem cells offers an alternative route for cell delivery, which may avoid microcirculatory problems. Unfortunately, low retention efficiency is still significant. Mechanical leakage following direct intracardiac injection is 33 and 89% in non-beating and beating porcine hearts, respectively [75]. Only 3% of endothelial progenitor cells were detected in the infarcted rat heart right after injection [3], while approximately 7% of myoblasts survived by 72 h following intracardiac injection into the infarcted mouse heart [73].
Long term follow-up study also confirmed the low survival rate of exogenous stem cells in the ischemic heart. In a mouse coronary ligation model, less than 2% of the injected embryonic stem cells survived 8 weeks after myocardial infarction [41]. Interestingly, instead of turning into caridomyocytes, the surviving stem cells differentiated into endothelial cells, forming blood-carrying microvessels [41]. Of note, stem cells from different sources may differ in the ability to incorporate into or form new capillaries and/or arterioles [29]. Clinical study also confirmed that progenitor cell transplantation promoted restoration of microvascular function in the infarct-related artery [20]. On the other hand, cardiac function was deteriorated by elimination of endothelial-committed cells following transplantation of bone marrow mononuclear cells into the infracted heart, but not affected by deletion of cardiac-committed cells [87]. Thus, stem cell-mediated angiogenesis and improvement of cardiac perfusion in the infarct or border zone is more likely via a mechanism involving cardiac functional improvement rather than through direct cardiac regeneration.
Interaction between inflammation and stem cells
The interaction between system/local inflammation and stem cells significantly influences the survival and function of stem cells. The SDF-1/CXCR4 axis is a well-known signaling pathway that directs the homing of stem cells to the infarct area or border zone in the setting of ischemic cardiomyopathy [57, 88]. However, the specificity of this pathway in stem cell recruitment has to be interpreted carefully, as SDF-1 was also reported as a potent chemotactic fact for a variety of cells, such as T cells [30], B cells [16], dendritic cells [71], mast cells [42] and eosinophils [52]. In fact, SDF-1 plays a critical role in regulating the trafficking of all the CXCR4+ haemato/lymphopoietic cells in inflammation [35]. In the absence of injury, even forced over-expression of SDF-1 is not sufficient to recruit stem cells [2, 58]. Malek et al.[46] found that the severity of acute inflammation is critical for stem cell recruitment in a murine myocarditis model. Delivery of embryonic stem cells at the peak of inflammation (the time point with highest cytokine production) following induction of myocarditis resulted in the highest level of stem cell engraftment in the heart and greatest functional improvement 3 month later. Pretreatment of stem cells with TNF-alpha, a well-known proinflammatory cytokine, enhanced MSC engraftment into infracted myocardium [32]. Recently evidence demonstrated that TNF-alpha has diverse effects on stem cell function via different subtypes of TNF receptors. Ablation of TNF receptor type 1 (TNFR1), but not TNF receptor type 2 (TNFR2) or both receptors, improved MSC-mediated cardiac protection. Infusion of TNFR1 knockout MSCs was associated with decreased proinflammatory cytokines and increased protective vascular endothelial growth factor (VEGF) [31, 74]. TNFR2 expressed in bone marrow-derived stem cells was required for the ischemia-induced endothelial progenitor cell-mediated neovascularization [23]. Interestingly, TNF-alpha is also required for the activation of MSCs and the production of VEGF, which is mediated by Toll-like receptor 2 (TLR2) [1]. In addition to their regenerative ability, the antiinflammation and immunomodulation effects of stem cells are attracting investigative attention in various diseases [10, 37, 44, 49, 84, 91]. In the setting of acute myocardial infarction, continuous secretion of the anti-inflammatory cytokine IL-10 by transplanted stem cells was reported to improve cardiac function without affecting the infarct size, but associated with reduced T cell infiltration as well as T cell-mediated inflammation [12]. The positive immunomodulatory effect by IL-10 secreting stem cells was considered as a new mechanism of stem cell-based therapy that is distinct from both tissue regeneration and paracrine effects [11]. Salem et al. [66] summarized the immunosuppressive effects of MSCs on T cells, natural killer cells and dentritic cells. Recent evidence suggests that the inhibitory effect on T cell proliferation and secretion of interferon-gamma is mediated by stem cell-secreted prostaglandin E2 (PGE2), while CD14+ monocyte promoted the immunosuppressive effects of stem cells via IL-1beta dependent pathways [82]. Also, stem cell-secreted PGE2 was reported to play a central role in inhibition of monocyte-derived dentritic cell maturation [71]. These observations matched with the beneficial role of PGE2 in myocardial I/R injury or acute myocardial infarction [17, 27]. Intriguingly, selective deletion of PGE2 receptor EP4 in cardiomyocytes resulted in reduced cardiac function with less fibrosis following myocardial infarction [61], which indicated stem cells/PGE2 may have diverse effects on inflammatory cells and cardiomyocytes.
Summary
The last decade has witnessed a boost of interest in stem cell-based therapies by both basic scientists and clinicians. In spite of the widespread studies in this area, stem cells-based therapy for ischemic heart diseases is still in its infancy. An effective treatment of patients with stem cells is currently not in sight, and the mechanisms of stem cell-mediated effects are not yet fully understood. In particular, the outcomes desired for stem cell-based therapies may be complicated by the diverse effects of stem cells on inflammatory cells and cardiac cells, as well as the behavior and fate of stem cells at the microvascular level. Further investigations are required on the interaction between stem cells and inflammatory cells and the subsequent effects on the fate of cardiomyocytes in the microvasculature and beyond to improve on delivery of these therapies.
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