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doi: 10.1097/shk.0b013e318058a817
Review Articles

STEM CELL MECHANISMS AND PARACRINE EFFECTS: POTENTIAL IN CARDIAC SURGERY

Crisostomo, Paul R.*; Wang, Meijing*; Markel, Troy A.*; Lahm, Tim; Abarbanell, Aaron M.*; Herrmann, Jeremy L.*; Meldrum, Daniel R.*†§

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Departments of *Surgery and Physiology, Indiana University School of Medicine, Indianapolis Department of Medicine and the §Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana

Received 05 Feb 2007; first review completed 15 Feb 2007; accepted in final form 05 Mar 2007

Address reprint requests to Paul R. Crisostomo, MD, 545 Barnhill Drive, Emerson Hall 203, Indianapolis, IN 46202. E-mail: pcrisost@iupui.edu.

This work was supported in part by NIH R01GM070628, NIH K99/R00 HL087607701, NIH NRSA, AHA Grant-in-aid, and AHA Postdoctoral Fellowship 0526008Z.

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Abstract

Heart disease remains the leading cause of death in the industrialized world. Stem cell therapy is a promising treatment modality for injured cardiac tissue. A novel mechanism for this cardioprotection may include paracrine actions. Cardiac surgery represents the unique situation where preischemia and postischemia treatment modalities exist that may use stem cell paracrine protection. This review (1) recalls the history of stem cells in cardiac disease and the unraveling of its mechanistic basis for protection, (2) outlines the pathways for stem cell-mediated paracrine protection, (3) highlights the signaling factors expressed, (4) explores the potential of using stem cells clinically in cardiac surgery, and (5) summarizes all human stem cell studies in cardiac disease to date.

ABBREVIATIONS-MSC- mesenchymal stem cell; VEGF- vascular endothelial growth factor; HGF- hepatocyte growth factor; FGF- fibroblast growth factor; TGF- transforming growth factor; LV- left ventricular; LVEF- left ventricular ejection fraction; MI- myocardial infarction; PCI- percutaneous coronary intervention

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EVOLUTION OF STEM CELL THERAPY IN CARDIAC DISEASE

In developed countries with aging populations, the prevalence of heart failure continues to escalate and remains the major cause of mortality. Despite modern revascularization and pharmacological strategies, current therapy has been limited in preventing the progression of ventricular remodeling largely due to loss of a critical number of cardiomyocytes and rare mitotic myocyte division and regeneration (1). Thus, recent interest has focused on cell-based cardiac repair, with particular emphasis on stem cells to replace or reverse the loss of contractile cells (2).

Stem cells are defined as unspecialized or undifferentiated precursor cells with the capacity for long-term division without differentiation (self-renewal) and the power to differentiate into multiple different specialized cell types (pluripotency) (2). In 1998, Ferrari et al. (3) first described bone marrow stem cell transplantation into injured muscle tissue resulting in regeneration of damaged fibers. Subsequent experimental studies in infarcted myocardium suggested that application of stem cells resulted in positive remodeling, improved myocardial function, and regeneration of healthy functional cardiac tissue (4, 5). It was hypothesized that undifferentiated stem cells regardless of lineage (hematopoietic, marrow, etc) transformed or transdifferentiated into an unexpected phenotype, de novo cardiac myocytes.

However, we now appreciate that this stem cell-mediated protection probably did not result from transdifferentiation into cardiac myocytes (6-8). Indeed, acute application of mesenchymal stem cells (MSCs) into injured cardiac (9, 10) and renal (11) tissue attenuated I/R injury without evidence of differentiation. These acute protective effects less than 72 h after injury precluded cardioprotection due to meaningful donor cell myogenic differentiation and regeneration. In further support of differentiation-independent cardioprotection, in vitro studies of cardiomyocytes injured in response to monocyte chemoattractant protein 1 (12) or hypoxia (13) also demonstrated protection with MSC-derived conditioned medium that did not contain stem cells. When infused into infarcted hearts, MSC-conditioned medium alone limited infarct size and improved functional recovery of both the left (14) and right ventricles (15). Mesenchymal stem cell-conditioned medium has also been shown to attenuate hypoxic pulmonary vasoconstriction (16). Finally, whereas some argue that fusion may give rise to hybrid cardiac cells after stem cell transplantation, generally, the numbers have been too few to influence contractile function (17, 18). Taken together, these data suggest that stem cells may improve cardiac contractile performance and limit myocardial infarct size not via differentiation or transdifferentiation but rather via complex paracrine actions.

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STEM CELL TYPES

Not all stem cells are created equal. The last decade of exponential stem cell research has led to a multiplicity of cell types identified that differ in potency, self renewal, characteristics, and function. Although no uniform nomenclature and classification system exists, conventional terminology broadly stratifies stem cells by origin (adult versus embryonic) and potency (pluripotent, multipotent, etc). The following is a selection of the most widely studied stem cells under investigation today.

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Embryonic stem cells

In 1998, investigators began to study and characterize human embryonic stem cells (ESCs). However, due to ethical, legal, and political issues, the National Institutes of Health currently only funds research using human ESCs derived from lines before August 9, 2001. Embryonic stem cells, derived from the inner cell mass of the blastocyst, can become all cell types of the body because they are pluripotent. Furthermore, large numbers of ESCs can be relatively easily grown in culture and can proliferate for a year or theoretically indefinitely in the laboratory without differentiating. Embryonic stem cells are characterized by the expression of CD30 antigen and several other unique intracellular proteins. However, ESC treatment carries with it the possibility of unregulated growth and subsequent cancer. Although injecting ESCs into immunocompromised hosts produces teratomas that contain differentiated derivatives of all three germ layers, injecting ESCs into normal hosts may also cause teratocarcinomas that may cause undue sickness requiring euthanasia. Moreover, because ESCs are derived from foreign blastocysts, ESCs may also be rejected by the recipient immune system.

In contrast, adult stem cells are multipotent-generally limited to differentiating into cell types of their tissue of origin. Adult stem cells also have a lower capacity for self-renewal and can be more difficult to expand in culture. Adult stem cells have the advantage of lower oncogenic potential and the ability to circumvent immune rejection because one can harvest autologous adult stem cells.

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Hematopoietic stem cells

Hematopoietic stem cells (HSCs), precursors to all blood lineages, are present in the bone marrow, placenta, and umbilical cord. Hematopoietic stem cells have been used in bone marrow transplants for more than 40 years, allowing investigators to thoroughly characterize and identify HSCs. For example, it is widely known that expression of the CD34 antigen is a common characteristic of HSCs and progenitors, and that lineage-committed progenitor cells make up most CD34+ cells (19). However, several decades of research has also allowed recognition of its disadvantages. It is currently very difficult to grow HSCs in culture because they tend to differentiate into more advanced cell types very quickly. Hematopoietic stem cell harvest is also difficult because only 1 in every 10,000 bone marrow cells is believed to be a stem cell, and this ratio falls to 1 in every 100,000 for blood cells (20, 21).

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Mesenchymal stem cells

Mesenchymal stem cells (MSCs), also known as bone marrow stromal cells (BMSCs), are a relatively underexplored population of bone marrow-derived stem cells that may have advantages over the well-characterized HSC population (22). Mesenchymal stem cells demonstrate ease of isolation by simply attaching to the plastic on the bottom of the culture dishes and can grow for several weeks before they will differentiate into other cell types. Ready availability from small aspirates of donor bone marrow and their multipotent capacity for differentiation also make MSCs ideal for clinical applications (2, 23). Mesenchymal stem cells also demonstrate an innate ability to evade rejection, allowing not only autologous stem cell options but also allogeneic or even heterologous options as well. However, recent studies using MSCs vary in methods of isolation and expansion, making it difficult to compare study outcomes and resulting in uncertainty regarding the uniformity of studied MSC populations. Under strict criteria, MSCs are thought to adhere to plastic in standard culture conditions, to express CD29 and CD105, and lack expression of CD34 and CD45.

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Circulating progenitor cells

Circulating progenitor cells (CPCs) are derived from bone marrow, circulate throughout the peripheral blood, and include hematopoietic, mesenchymal, and endothelial progenitor cells. However, these progenitor cells are not true stem cells; they lack the multipotency of bone marrow HSCs and MSCs, and instead demonstrated a committed lineage phenotype. Recent research indicates that endothelial and hematopoetic CD34+ CPCs participate in neoangiogenesis after tissue ischemia has occurred (24).

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STEM CELL PARACRINE PATHWAYS

The mechanistic paracrine underpinnings for the enhancement of cardiac function via stem cell transplantation are not fully understood. However, four mechanisms have been postulated. First, stem cells may produce local signaling molecules that limit cardiomyocyte apoptosis, improve perfusion, and enhance angiogenesis to chronically ischemic tissue. When transplanted into injured tissue, the stem cell faces a foreign inflammatory environment and may release substances that limit local inflammation to enhance its survival. In fact, expression profiling of adult progenitor cells reveals characteristic expression of genes associated with enhanced DNA repair, upregulated antioxidant enzymes, and increased detoxifier systems (25, 26). When exposed to either hypoxia or LPS, MSC significantly increase release of vascular endothelial growth factor (VEGF) (27), which not only may improve regional blood flow (28) in ischemic hearts but also may promote stem cell self-survival (29).

Stem cells in a second pathway may promote salvage of tenuous or malfunctioning cardiomyocytes at the infarct border zone. Jaquet et al. (30) found that injection of MSC into a cryo-induced infarct reduced myocardial scar width 10 weeks later. Furthermore, evidence exists that both endogenous and exogenous stem cells may be able to "home" or migrate into the scar from the site of injection or infusion. Mesenchymal stem cells in the bone marrow can be mobilized, target myocardial infarction (MI), and differentiate into myocytes (31). This homing may depend on myocardial expression of stromal cell-derived factor 1 (32) and/or monocyte chemoattractant protein 3 (33).

Third, stem cell transplantation may alter the extracellular matrix, resulting in more favorable postinfarct remodeling, strengthening of the infarct scar, and prevention of deterioration in cardiac performance. Acute human (10) and murine (9) MSC infusion before ischemia have been shown to improve myocardial-developed pressure, contractility, and compliance after I/R injury and decrease end-diastolic pressure. Similarly, direct human MSC injection into ischemic hearts decreased fibrosis, left ventricular (LV) dilation, apoptosis, and increased myocardial thickness with preservation of systolic and diastolic cardiac function without evidence of myocardial regeneration (34). Mesenchymal stem cells may achieve this improved cardiac function by acutely increasing cellularity and decreasing production of extracellular matrix protein collagen type I, collagen type III, and tissue inhibitor of metalloproteinase 1 (35, 36), resulting in positive remodeling and function.

Finally, exogenous stem cell transplantation may activate resident cardiac stem cells. Recent work has demonstrated the existence of cardiac stem cell-like populations in adult hearts (4, 37). These cardiac stem cells possess a hepatocyte growth factor (HGF) receptor and an insulin-like growth factor 1 receptor that can be activated to induce their migration, proliferation, and promote restoration of dead tissue and improved cardiac function in damaged hearts (38). Mesenchymal stem cells have also been shown to release HGF and insulin-like growth factor 1 in response to injury (39), which, when transplanted into ischemic tissue, may subsequently activate resident cardiac stem cells.

Although the definitive mechanism basis for cardioprotection via stem cells remains unclear, one can surmise that stem cells may mediate cardioprotection via paracrine actions on cardiomyocytes and cardiac stem cells as well as direct effects on the extracellular matrix and infarct zone (Fig. 1). Improved understanding may allow earlier therapeutic application, maximization of paracrine protection, and minimization of deleterious consequences for patients with myocardial ischemia.

Fig. 1
Fig. 1
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STEM CELL PARACINE SIGNALING MOLECULES

Stem cells transplanted into injured myocardium express several signaling factors that are involved in angiogenesis, cytoprotection, and survival. Vascular endothelial growth factor, HGF, fibroblast growth factor (FGF), and transforming growth factor (TGF) are key signaling factors in stem cell-mediated repair.

Vascular endothelial growth factor is a strong promoter of angiogenesis (40-43). Mesenchymal stem cells exposed to hypoxia, LPS, and H2O2 have demonstrated increased expression of VEGF (44). Human adipose stem cells also secrete VEGF in response to hypoxia and LPS in vitro (45). Futhermore, VEGF in bone marrow stem cell therapy has shown an important role in conferring myocardial protection from ischemia (46). Rehman et al. (45) found that media derived from hypoxic MSCs in culture significantly increased endothelial cell growth and reduced endothelial cell apoptosis. Tang et al. (28) determined that MSC implantation significantly elevated VEGF expression and regional blood flow in ischemic hearts. Furthermore, Wang et al. (47) demonstrated that VEGF overexpressing bone marrow stem cells demonstrated greater cardioprotection than controls. In addition to protective paracrine effects, VEGF release may also protect the stem cell itself in an autocrine fashion (29). Determining whether stem cell release of VEGF confers protection to surrounding tissue by reducing apoptosis (45, 48, 49), decreasing proinflammatory cytokines (50-52), or other mechanistic pathways (53-56) such as p38 MAPK (39) requires further investigation. Nevertheless, these studies suggest that MSCs may confer protection by moderating local inflammation and stimulating endogenous repair mechanisms via the release of protective substances such as VEGF.

Although originally associated with liver regeneration, HGF is now recognized as a growth factor affecting various tissues and cell types. Adipose progenitor cells have shown to increase HGF secretion in hypoxic conditions (45) and in response to TNF-α(39). These studies suggest that progenitor cells may exert protection by regulating local inflammation and repair mechanisms through the secretion of protective factors such as HGF (57). Hepatocyte growth factor has been observed to improve cell growth and to reduce cell apoptosis (45). Hepatocyte growth factor exerts the beneficial effect on neovascularization and tissue remodeling (28, 57, 58). Hepatocyte growth factor also mobilizes CPCs and cardiac stem cells from the surrounding myocardium into the dead tissue (59, 60).

Fibroblast growth factors are also constitutively expressed by stem cells (61-63). Fibroblast growth factors play an important role in embryonic development and, in the adult, may enhance stem cell self-renewal and differentiation into end-organ tissue (64). Specific members of the FGF signaling family may also be involved in the promotion of endothelial cell proliferation. Fibroblast growth factor 2 has been shown to be intimately involved with angiogenesis and may be a more potent angiogenic factor than VEGF (65). After MSC injection into ischemic tissue, increased tissue FGF2 and VEGF as well as improved perfusion and function were observed (62). In addition to angiogenesis, FGF2 expression may be increased in response to injury and enhance stem cell self-survival (66). Indeed, transfection of MSCs with FGF2 has been shown to improve stem cell survival under hypoxic conditions (67). Thus, FGF may be an important paracrine signaling molecule in stem cell survival, self-renewal, differentiation, and protection.

Transforming growth factor β (TGF-β) may also be involved in stem cell differentiation and protection (68). Recent studies have confirmed basal and stimulated MSC expression of TGF-β (61, 69). Transforming growth factor β may up-regulate cardiac-specific transcription factors and increase cardiac differentiation (70). Consequently, stem cells exposed to TGF-β may confer additional cardioprotection to infarcted myocardium (71) Nevertheless, evidence also exists regarding the inhibitory effects of TGF-β on stem cells. Transforming growth factor β may inhibit in vitro growth and proliferation of HSCs (72, 73). Thus, a stem cell's proproliferative or antiproliferative, proapoptotic or antiapoptotic response to paracrine TGF-β signaling remains to be clarified and may depend on stem cell type, differentiation stage, or other environmental factors.

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MAXIMIZING STEM CELL PARACRINE PROTECTION

Enhanced survival of transplanted stem cells may increase their cytoprotective efficacy. Although few reports have quantified stem cell survival after transplantation, donor stem cell survival may be as low as 1% 24 h after transplantation (74, 75), possibly due to a hostile, nutrient-deficient, inflammatory environment within damaged myocardium. Dai et al. (76) determined that, although MSC transplantation after myocardial infarct improved early global LV function, the benefit of stem cell treatment was lost at 6 months. This survival limitation may limit the sustained reparative capacity of stem cells in vivo and reduce clinical availability depending on the quantity procured from autologous cell harvest and the time required for ex vivo expansion in culture. Recently, Uemura et al. (77) determined that MSC survival and, indeed, subsequent myocardial protection may depend on Akt activity. Activation of Akt is associated with enhanced cell cycling, cellular proliferation, and survival by targeting apoptotic caspases. Indeed, transduction of Akt1 into MSCs and subsequent transplantation of Akt overexpressing stem cells into injured myocardium decreased inflammation, apoptosis, and increased functional recovery (78). Moreover, conditioned media derived from Akt modified MSC but, without cells, also conferred cardioprotection on cardiomyocytes and experimentally induced MI (13, 14). Thus, Akt modification of stem cells before transplantation may enhance stem cell survival and cardioprotective effects via paracrine pathways.

Similar enhancement of stem cell cardioprotection has been observed with VEGF transduction. Matsumoto et al. (79) transduced VEGF into MSCs, transplanted VEGF-modified MSCs into hearts after coronary ligation, and found decreased infarct size and improved functional recovery. Furthermore, Yang et al. (80) determined that VEGF genetically modified MSCs conferred greater cardioprotection than nonmodified MSCs as measured by capillary density and infarct size. Vascular endothelial growth factor is a critical growth factor in angiogenesis, and enhancing its paracrine expression by stem cells may lead to improved outcomes.

Preconditioning, injury-induced protection from subsequent injury, has proven to be a powerful form of cardioprotection, but until recently, its effects on stem cells were unclear. Jiang et al. (81) preconditioned MSCs with hypoxia, transplanted the stem cells into ischemic myocardium, and observed enhanced survival and cytoprotective capacity. The preconditioning hypoxic stimulus may stimulate the synthesis of VEGF (27) and increase activation of Akt and eNOS (77). Thus, hypoxic preconditioning of stem cells may cause the up-regulation of prosurvival proteins and angiogenic growth factors that increase paracrine-mediated cardioprotection, suggesting a role for ex vivo priming of stem cells before therapeutic use.

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STEM CELLS IN CARDIAC SURGERY

Cardiac surgery affords a unique opportunity to examine preischemic and postischemic stem cell treatment modalities. Precognition of surgical induced ischemia allows stem cell transplantation before, during, and after ischemia. Indeed, we have demonstrated that acute infusion of mesenchymal stem cells and preadipocytes before ischemia improved functional recovery, decreased inflammation, and decreased proapoptotic signaling from I/R injury (9, 10, 15). Potentially, one can capitalize on the paracrine-protective abilities of stem cells by infusing stem cells or stem cell-free media into the heart before the commencement of cardiopulmonary bypass (CPB) and during CPB. In fact, any cardiac procedure requiring CPB (on pump cardiac surgery, cardiac transplantation) also provides the opportunity for postischemic stem cell treatment. Several experiments have shown that stem cells may confer cardioprotection when given after an ischemic event (5, 34, 77). Thus, foreknowledge of surgical induced ischemia in cardiac surgery allows the ability to examine the ideal timing for stem cell administration.

Cardiac surgery also presents the opportunity to determine the ideal mode for stem cell delivery. Several investigations have observed cardioprotection via intramyocardial injection of stem cells (18, 82). A smaller number of studies have also demonstrated myocardial protection via intravenous and intracoronary delivery of stem cells (39, 83, 84). However, unlike cardiac surgery, percutaneous intravenous or intracoronary delivery does not have direct visualization of infarcted tissue. Thus, investigations have recently centered on stem cell homing as a method of mobilizing stem cells and targeting injured tissue (85, 86). Granulocyte colony-stimulating factor (G-CSF) has been widely studied (87, 88) and promotes the mobilization of bone marrow-derived stem cells in the setting of MI, leading to improvements in myocardial function (89). Nevertheless, two large randomized trials used G-CSF to mobilize stem cells in the setting of MI and did not find significant benefit. In fact, G-CSF has been associated with restenosis after coronary stenting (90). Intracoronary infusion of stem cells, possibly due to microembolization, has also been noted to increase myocardial ischemia (91). In contrast, stem cell therapy via direct surgical implementation does not require homing or intracoronary infusion. Currently, no study has compared head-to-head the modes of delivery for stem cells, and no clinical studies have attempted intramyocardial injection of stem cells. Cardiac surgery would permit a safe controlled method to directly visualize ischemic tissue and intramyocardial injection of stem cells and provides potential for comparing mode of delivery clinically.

Cardiac surgery patients also compose a unique population where investigation of the ischemic disease process and the ideal stem cell quantity and type is possible. Although no study has addressed the ideal quantity of stem cells necessary to confer cardioprotection, recent investigations have noted arrhythmogenesis after stem cell infusion (92). However, LV assist device patients may be less susceptible to arrhythmogenesis and, thus, may be a patient subset suitable to determine the ideal stem cell quantity considering safety and efficacy. Embryonic stem cells may be the most potent stem cells with greater paracrine and regenerative capacity. However, ESC potency is accompanied by tumor formation (93). Transplant patients may be suitable patients for investigation of ESCs before transplantation because cardiectomy at time of transplantation might rectify adverse tumor formation. Removal of the patient's native heart at transplantation also allows molecular and histological study of the pretransplant stem cell contribution to myocytes, vessels, or whether stem cells simply increase growth factor production. In particular, cardiac transplant patients also offer the opportunity for direct surgical visualization of stem cell injection because many require a ventricular assist device as a bridge to transplant. In addition to pretransplant patients, posttransplant patients may also be appropriate candidates for ESC therapy because their immunosuppressive medications may help prevent ESC rejection. Sex-mismatched organ posttransplant patients and their inherent chimerism may also be useful in the assessment of stem cell contribution and proliferation. One can easily identify autologous transplanted stem cells by chromosome verification (94). Thus, surgical cardiac patients may have advantages that decrease their potential morbidity in stem cell treatments.

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CLINICAL TRIALS

Despite our lack of understanding regarding the mechanism of stem cell cardioprotection, a number of randomized clinical trials have been completed using bone marrow stem cells. Although these early trials were designed to assess safety rather than efficacy, it is interesting to note the varying results regarding cardioprotection. From 2002 to 2004, the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trial enrolled 59 acute myocardial patients who received either CPCs or bone marrow stem cells 5 days after percutaneous coronary intervention (PCI); however, no control group was studied. Angiographic assessment of LV ejection fraction (LVEF) demonstrated significant overall improvement at 4 months compared with baseline in both stem cell groups. Magnetic resonance imaging (MRI) at 1 year demonstrated improved LVEF and decreased infarct size compared with baseline in both stem cell groups. No significant difference in outcome was observed between stem cell groups (95). The promising and safe results of the TOPCARE-AMI trial motivated further clinical trials compared with control groups.

Reported in 2004, the Benefits of Oxygen Saturation Targeting (BOOST) trial randomized 60 acute myocardial infarct patients randomized post-PCI to standard medical therapy or standard medical therapy with intracoronary infusion of bone marrow stem cells 5 days after PCI. Magnetic resonance imaging to determine LVEF and infarct size revealed that bone marrow stem cells conferred significant improvement (6.7%) of LVEF at 6 months over controls, but did not provide long-term benefit on LV systolic function because the control group had undergone a gradual recovery of LVEF by 18 months (96). In another study from 2003 to 2004, Janssens et al. (97) randomized 67 patients 1 day post-PCI to BMSC intracoronary infusion or intracoronary placebo. Unlike the BOOST trial, Janssens et al. harvested BMSC in all patients and infused intracoronary placebo in the control group. They determined that LVEF, as measured by cardiac MRI at 4 days and 4 months, was not significantly different between the control and treated groups. However, they did determine that BMSC infusion reduced infarct volume at 4 months (97). Reported in 2005, the Autologous Stem Cell Transplantation in Acute Myocardial Infarction trial prospectively randomized 100 acute myocardial infarct patients to control or intracoronary bone marrow stem cells 5 to 8 days after PCI. Although they determined that intracoronary stem cell infusion was safe, no difference was observed as measured by MRI of heart function (98).

The largest clinical trial, the double-blind multicenter REPAIR-AMI trial reported in 2006, enrolled 204 acute myocardial infarct patients and randomized them to either placebo or intracoronary infusion of bone marrow stem cells 3 to 7 days after PCI. Angiography assessment of LVEF found an early beneficial (2.5%) effect of stem cells at 4 months (99). At 1 year, the combined clinical end point of death, recurrence of MI, and revascularization procedures were significantly better in the stem cell group but was not significant for each individual clinical end point; LVEF was not measured at 1 year. Interestingly, a subset of patients whose baseline LVEF was less than the median derived the most benefit from stem cell therapy (5.0% improvement in LVEF versus controls). Animal studies have demonstrated that hypoxia, TNF, and hydrogen peroxide seem to enhance the production of MSC-derived cardioprotective factors (44, 100). Thus, the increased stem cell growth factor expression in response to hypoxia might explain the observation that acute MI patients with more severe cardiac dysfunction (and, presumably, a larger ischemic burden) exhibit the greatest benefit from intracoronary MSC.

Although the aforementioned trials addressed acute MI, few have studied the effects of stem cell protection in chronic ischemic heart disease. Most recently, the TOPCARE-CHD trial randomized 75 patients more than 3 months after myocardial infarct to intracoronary infusion of bone marrow stem cells, circulating blood progenitor cells, or none. At 6 months, patients who received bone marrow mesenchymal stem cells demonstrated a 2.9% increase in LVEF versus controls and patients infused with circulating blood progenitor cells. Although no long-term data were reported, the bone marrow stem cell-infused patients achieved this small benefit while concomitantly following standard medical therapy (101).

Collectively, it seems that intracoronary bone marrow MSC infusion is a safe treatment modality. However, it also seems that BMSC intracoronary infusion in AMI patients has either a negative or minimal beneficial effect over placebo, which contradicts much of the preclinical animal research. Several reasons for this discrepancy may exist.

Recent research indicates that preexisting comorbidities may also affect stem cell survival and engraftment. Preclinical stem cell animal studies have predominantly been conducted in normal healthy animals with experimentally induced injury. In contrast, recent clinical stem cell studies examined AMI patients who have varying degrees of comorbidities that may not only have led to AMI but stem cell impairment as well. Several studies have shown that injury may suppress bone marrow function (102, 103). Rota et al. (104) and others determined that diabetes promotes cardiac stem cell senescence and apoptosis. Similarly, Awad et al. and others (105, 106) found that endothelial progenitor cells harvested from animals with obesity and diabetes type II exhibited angiogenic dysfunction. Heeschen et al. (107) found that chronic ischemic heart disease also reduced bone marrow stem cell angiogenesis. These results indicate that chronic stem cell exposure to stress may reduce its functional capacity, and that autologous BMSC in AMI patients may not be ideal.

Other trial-specific causes may also explain the little efficacy seen with human stem cell therapy in AMI patients. In the BOOST trial, bone marrow harvest was not limited to stem cells and may also have included inflammatory cells, which could have caused adverse effects in infarcted myocardium. In the Autologous Stem Cell Transplantation in Acute Myocardial Infarction trial, baseline EF was only mildly diminished after AMI and may have made differences between treatment and control groups more difficult to appreciate. In the study by Janssens et al. (97), early reperfusion occurred as well as early BMSC therapy, which could have mitigated potential cell-mediated effects on functional recovery. These uncertainties regarding stem cell treatment further highlight the need to address timing, delivery, cell type, and optimum dose.

Furthermore, because these clinical phase 1 trials were designed to assess safety foremost, they lacked the power to critically assess efficacy and myocardial protection seen in other treatment phase 2 and phase 3 clinical trials. Although this lack of power makes it difficult to identify subgroups that may indeed benefit from BMSC therapy, AMI patients with more severe cardiac dysfunction seem to exhibit the greatest benefit from intracoronary MSC. Furthermore, BMSC therapy may have an acute but not prolonged beneficial effect depending on patient cardiac function. However, the mechanism behind this cardioprotection, indeed, whether this protection was paracrine derived, remains unclear.

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CONCLUSION

Stem cell therapy has emerged as an exciting new area of medicine and surgery. Stem cells may mediate their beneficial cardiac effects in part by paracrine mechanisms. Paracrine-mediated actions have proven to potentiate positive myocardial remodeling, improved function, reduced apoptosis, and decreased infarct size. Intriguingly, this paracrine protection may be enhanced by ex vivo modification. Nevertheless, several unknowns regarding mechanism and optimal treatment methodology exist. Cardiac surgery represents the unique opportunity where these unknowns as well as timing, delivery modality, and cell type may be tested. Clinical trials in both acute and chronic myocardial ischemia indicate that stem cells treatments are safe, although future trials designed to assess efficacy and protection remain to be seen. Continued enthusiasm coupled with rigorous scrutiny may enable earlier widespread therapeutic application in myocardial disease.

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Keywords:

Cardioprotection; HGF; mesenchymal; MSC; signaling; VEGF

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