Abstract
Advances in diagnosis and treatment have dramatically impacted morbidity and mortality from cardiovascular disease over the past several decades.1 The discovery in 1960 of stem cells capable of regeneration and repair sparked interest in a new mode of therapy for heart disease beyond pharmaceuticals and cardiac devices.2 Over the past 10 years, work has focused on five key cell types - the endothelial mononuclear progenitor cell, the autologous skeletal myoblast, the allogeneic mesenchymal stem cell, the resident cardiac stem cell, and the human embryonic stem cell - as potential therapeutic agents, which may further contribute to gains in treating cardiovascular disease. This chapter aims to review these cell types, their preclinical underpinnings, the nascent clinical studies, and limitations observed in their use.
1 Introduction
Advances in diagnosis and treatment have dramatically impacted morbidity and mortality from cardiovascular disease over the past several decades.1 The discovery in 1960 of stem cells capable of regeneration and repair sparked interest in a new mode of therapy for heart disease beyond pharmaceuticals and cardiac devices.2 Over the past 10 years, work has focused on five key cell types - the endothelial mononuclear progenitor cell, the autologous skeletal myoblast, the allogeneic mesenchymal stem cell, the resident cardiac stem cell, and the human embryonic stem cell - as potential therapeutic agents, which may further contribute to gains in treating cardiovascular disease. This chapter aims to review these cell types, their preclinical underpinnings, the nascent clinical studies, and limitations observed in their use.
2 Endothelial Progenitor Cells/Bone Marrow-Derived Mononuclear Cells
2.1 Background
The pathobiology of atherosclerosis has been largely attributed to processes of repeated vascular injury leading to plaque development and expansion, subsequent tissue ischemia, and ultimately infarction.3 More recently, the discovery of a population of endogenous mononuclear cells that reside in the bone marrow mobilize in response to tissue injury, and repair injured vascular tissue has challenged the classic Ross hypothesis, offering the possibility of another mode of treating atherosclerotic vascular disease. The precise identity of these so-called endothelial progenitor cells (EPCs) remains elusive. EPCs have thus necessarily been defined by their functions - that they originate in the bone marrow, circulate in peripheral blood, home to sites of vascular injury, and participate in new blood vessel formation.4 Asahara and colleagues in 1997 provided the strongest evidence that new blood vessel formation is partly attributable to a population of bone marrow-derived monocytes. CD34-positive mononuclear cells isolated from humans demonstrated an endothelial phenotype in vitro. Moreover, these cells participated in neo-angiogenesis in a mouse hindlimb ischemia model,5 thus suggesting a possible therapeutic role for regeneration after ischemic vascular injury.
Preclinical work has shown that exogenously administered EPCs home to areas of ischemia or infarct and participate in tissue regeneration or repair. Kalka and co-workers described the first use of EPCs in therapeutic neovascularization when human EPCs were transplanted into athymic nude mice in a model of hindlimb ischemia.6 Blood flow recovery and capillary density was reported to markedly improve. Human EPC transplanted into ischemic regions of a rat model of myocardial infarction resulted in improvements in left ventricular function.7 In a swine model of chronic myocardial ischemia, coronary collateral development and left ventricular ejection fraction improved after transplantation of autologous CD34-positive mononuclear cells.8 Moreover, other work has shown that transplanted EPCs injected after myocardial infarct may home to infarct border zones.9 When athymic nude rats were injected with radiolabeled human EPCs from peripheral blood, radioactivity was measured in cardiac tissues in greater proportion in infarcted hearts rather than in controls (although the total percentage was dwarfed by the percentage localizing to spleen and liver [1% vs. >70%]).
Although investigators initially hypothesized that EPCs directly participate in the formation of new blood vessels at sites of injury, the true mechanism of repair remains to be fully described. Three potential mechanisms by which EPCs exert influence on injured tissue include differentiation, cell fusion, and paracrine effects.10 Pathologic correlations show that areas of infarcted myocardium injected with autologous bone marrow derived mononuclear cells have a higher capillary density with cellular changes including hyperplasia of pericytes, mural cells, and adventitia.11 The presence of contractile proteins in these cells suggests an active process of angiogenesis. Still, the role that these EPCs play at sites of tissue injury remains controversial, with some work suggesting that they may perform tasks other than angiogenesis.12 Badorff and co-workers reported that peripheral blood mononuclear cells from healthy adults transdifferentiated in vitro into functionally active cardiomyocytes (expressing alpha-sarcomeric actinin, cardiac troponin I, atrial natriuretic peptide, and formation of gap junctions) when co-cultured with rat cardiomyocytes, via a cell-to-cell contact mechanism rather than cellular fusion.13 Other possible beneficial mechanisms of EPC repair via cell-cell signaling mechanisms are evident in work wherein co-incubation of bone marrow cells with cardiomyocytes in an ex vivo model of ischemia resulted in mitigation of cell death in a protein kinase C and p24 mitogen-activated kinase dependent process.14 Other work suggests that bone marrow-derived mononuclear cells contribute to new blood vessel formation in mouse hindlimb ischemia by a paracrine effect rather than directly incorporating into new vessel walls.15,16
2.2 Clinical Studies
While these repair mechanisms of EPCs continue to be elaborated, clinical studies of EPCs or of a broader population of bone marrow-derived mononuclear cells have been performed in settings of acute myocardial infarction, refractory angina, and chronic ischemic cardiomyopathy17–33 (Table 8.1). Although double-blinded placebo-controlled studies are limited, available data from over 350 subjects enrolled to date in various trials suggests that therapy with EPCs or bone marrow-derived mononuclear cells in these settings poses no excess hazard, and may result in improvements in ventricular function and remodeling. No single study has convincingly demonstrated convincing efficacy of cell therapy, yet generally favorable results have encouraged investigators to continue tackling key questions such as cell type, source of cells, delivery mode, dose, and timing of therapy.
Several studies have pursued a strategy of infusing autologous EPCs or bone marrow cells down the infarct-related artery of subjects several days after acute myocardial infarction, with the expectation that amplification of the existing repair mechanisms by delivery of a concentrated dose of cells to areas of recent injury might have demonstrable clinical benefit. Strauer and coworkers found that infusion of intracoronary autologous mononuclear bone marrow cells in the infarct-related arteries of 10 patients 5-7 days after acute transmural myocardial infarction resulted in improvements in regional contractility, reduction in infarct size, and improved perfusion.17 Cells were obtained by bone marrow aspiration with isolation of mononuclear bone marrow mononuclear cells via Ficoll and subsequent washing. CD133-positive cells (a more refined putative marker of EPCs) accounted for 0.65 ± 0.4% and CD34-positive cells 2.1 ± 0.28% of an average yield of 2.8(± 2.2) ± 107 cells. Notably, no patient in the study underwent revascularization of the infarct-related artery within 4 h of onset of symptoms, suggesting that improvements may be attributable to cell therapy effects rather than recovery of hibernating myocardium. Subsequently, Fernandez-Aviles and co-workers found improvement in end-systolic volume and improvement in LV function after infusing autologous bone marrow mononuclear cells down the infarct-related artery of patients suffering from acute ST-elevation myocardial infarction in a nonrandomized controlled trial.22 Cells were infused around 2 weeks after initial presentation, and no excess adverse events were noted in the study group. Though of similar trial design, the TOPCARE-MI trial examined whether adequate and effective doses of cells could be obtained from the peripheral circulation, thus avoiding the need for bone-marrow harvest. Fifty-nine subjects with acute myocardial infarction underwent intracoronary infusion of either circulating progenitor cells or bone marrow-derived mononuclear cells 4.9 ± 1.5 days after presentation.18,34 Though in the immediate follow-up two subjects developed recurrent infarction with one resultant death, in the 1 year follow-up period no significant ventricular arrhythmias or other adverse effects were observed. Both groups demonstrated favorable effects on LV remodeling as assessed by ejection fraction (50 ± 10%-58 ± 10%; p < 0.001) and end-systolic LV volume.
Randomized controlled trials of progenitor cell therapy have shown conflicting results with regard to efficacy. Improvements in left ventricular performance were observed by Wollert and co-workers when 30 subjects were randomized to receive intracoronary autologous BMC or placebo 4.8 days after presenting with acute ST elevation myocardial infarction.25 In comparison with 30 control subjects, cell therapy was associated with enhanced systolic function in segments adjacent to infarcted areas, without an excess risk of adverse clinical events. Long-term follow-up at 18 months, however, failed to show a persistent benefit of cell therapy over controls.26 In a multicenter study in which 204 subjects were randomized to intracoronary autologous bone marrow mononuclear cells or placebo, intracoronary injection of cells 3-7 days after acute myocardial infarction resulted in improvement in left ventricular ejection fraction measured by left ventricular angiography (5.5 ± 7.3% vs. 3.0 ± 6.5%; p = 0.01) in the treatment group.27 At 1-year follow-up, cell therapy was associated with a reduced risk of major adverse cardiovascular events (death, recurrence of myocardial infarction, and revascularization). In contrast, Lunde and co-workers failed to observe any significant difference in left ventricular ejection fraction by myocardial perfusion study or cardiac magnetic resonance imaging at 6 months in a randomized study of 100 patients receiving either intracoronary autologous bone marrow mononuclear cells or placebo 6 days after acute myocardial infarction.28
Likewise, studies questioning whether early delivery of cell therapy would affect efficacy and safety have found conflicting results. Evaluating the effects of emergent intracoronary infusion of bone marrow mononuclear cells on clinical outcomes, Ge and colleagues randomized 20 subjects to cell therapy infusion down the infarct-related artery vs. controls within 24 h of presentation with acute ST elevation myocardial infarction. As measured by echocardiography and myocardial perfusion study, both ventricular systolic function and perfusion improved in the cell therapy group at 6 months.30 In contrast, early cell therapy (within 24 h of reperfusion after acute myocardial infarction) using intracoronary autologous bone marrow mononuclear cells was not associated with significant improvement in left ventricular function or perfusion relative to standard medical therapy in 67 subjects randomized by Janssens and co-workers.29
Most progenitor cell therapy trials have employed a broad population of mononuclear cells, but more recent work has focused on whether a more narrowly defined population of progenitor cells might be isolated and used in therapy. Based on preliminary data suggesting that selected hematopoietic cell have a higher engraftment potential when compared with bone marrow-derived mononuclear cells, Bartunek and co-workers infused CD133-positive bone marrow mononuclear cells down the infarct-related artery of patients 11.6 ± 1.4 days after acute myocardial infarction.24 In comparison with controls, treated subjects evinced improvements in left ventricular performance as measured by ventriculography and myocardial perfusion studies. Ongoing studies examine whether isolated CD34-positive mononuclear cells benefit patients with acute myocardial infarction as well as chronic ischemic cardiomyopathy.
While most studies have obtained mononuclear progenitor cells from bone marrow niches, several studies have mobilized mononuclear progenitor cells from the bone marrow into the peripheral circulation using granulocyte colony-stimulating factor (G-CSF). Kang and co-workers found improvement in left ventricular structure and function at 6 months among patients treated with intracoronary peripheral blood mononuclear cells infused 10-11 days after acute myocardial infarction.32 No effect was noted in subjects with old (>14 days) myocardial infarction or in control groups. Similarly, Li and colleagues observed improvements in left ventricular ejection fraction and remodeling in a cohort of 35 nonrandomized subjects treated with G-CSF-mobilized autologous peripheral mononuclear cells infused down the infarct-related artery 7 days after presentation with acute myocardial infarction.33 Notably, there was a high incidence of complications with regard to mobilization, separation, and infusion. Ten other studies have employed G-CSF injections alone as a means of mobilizing bone marrow mononuclear cells in the setting of acute myocardial infarction with the aim of improving left ventricular function. According to a meta-analysis by Zohlnhofer and colleagues, among the 445 patients treated with this approach there was no significant improvement in left ventricular function over placebo.35
In 13 studies of progenitor cell therapy for acute myocardial infarction, doses of infused cells range from 10 million to 1 billion - in large part affected by available reservoir in the bone marrow and the degree of selection of progenitor cell subpopulations. Whether these doses are inadequate for clinical effect - thereby accounting for the modest clinical results seen across studies - remains unanswered. Meluzin and co-workers addressed the effect of dose of bone marrow mononuclear cells on clinical response in randomizing 66 patients to intracoronary infusion of high dose (108 cells), low dose (107 cells), or control at 7 days after acute myocardial infarction.31 Regional myocardial function improved in a dose-dependent manner as measured by tissue Doppler echocardiography and by gated myocardial perfusion imaging, thus suggesting that an adequate amount of delivered cells is important.
The potential role of progenitor cell therapy in chronic atherosclerotic coronary artery disease has been addressed in several studies (Table 8.2). Here, the route of delivery of cells varies from intracoronary infusion to direct intramyocardial injection. Strauer and co-workers found that intracoronary transplantation of autologous bone marrow mononuclear cells was associated with improvements in infarct size and global contractility (although in this cohort ejection fraction was relatively preserved).36 Versus controls, treatment with bone marrow mononuclear cells was associated with improvement in maximum oxygen uptake and regional fluoro deoxyglucose uptake. Perin and co-workers reported a durable improvement in left ventricular perfusion defects and exercise capacity in subjects treated with endomyocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy.37 Treatment of chronic ischemia with intracoronary peripheral mononuclear cells was associated with improvement in hibernating myocardium and infarct size at 3 months vs. controls.38 A study of similar subjects with refractory angina found improved perfusion and left ventricular function with endomyocardial injection of autologous bone-marrow-derived mononuclear cells.19 Similar results were reported in an unblinded series of subjects with endomyocardial injection of autologous bone marrow mononuclear cells.20 Mocini and colleagues describe a series of subjects with chronic ischemic cardiomyopathy finding improvement in left ventricular ejection fraction by echocardiography with direct injection of autologous bone marrow mononuclear cells into infarct border zones at the time of coronary artery bypass grafting.39 Endomyocardial delivery of CD133-positive bone marrow derived mononuclear cells at the time of coronary artery bypass grafting proved safe with modest improvements in ventricular performance at 6 months.21 Katritsis and co-workers infused a combination of so-called progenitor cells and mesenchymal cells from bone marrow in the coronary arteries of subjects suffering with chronic ischemic cardiomyopathy, finding improvements in left ventricular function measured by echocardiography and myocardial perfusion studies.40
2.3 Limitations and Future Directions
As mentioned, variables affecting the success of trials of progenitor cell therapy include the type and dose of cell, the mode of harvest, as well as the method and timing of delivery. Other possible limitations with the use of autologous bone marrow mononuclear cells rise from potential dysfunction in those subjects’ EPCs. Bone marrow derived mononuclear cells from subjects with chronic ischemic cardiomyopathy have less migratory and proliferative capacity in vitro, with reduced angiogenic capacity in vivo.41 While past studies have employed cellular admixtures obtained from bone marrow niches as reservoirs of cells with regenerative potential, ongoing studies have sought to refine the cell type by selecting for cell populations (such as CD34-positive cells) thought to be enriched for EPCs. Finally, the mechanism of potential benefit of progenitor cell therapy remains to be fully elucidated. Whether cells directly transdifferentiate into mature endothelial cells, fuse with existing vascular or muscle cells, or contribute angiogenic growth factors remains controversial.10
3 Mesenchymal Stem Cells - Autologous Skeletal Myoblasts
3.1 Background
The concept that skeletal myoblasts might serve as a source of myogenic cells was advanced by Taylor and coworkers in demonstrating that transplanted regenerative skeletal myoblasts incorporated into cardiac tissue and improve cardiac performance in a model of cryoinfarct in rabbits.42,43 Here, autologous skeletal myoblasts appeared to regenerate viable striated tissue among immature cardiocytes and was associated with improvement in ventricular compliance and diastolic performance; systolic changes were less robust.44–47 Benefits appear to extend to models of nonischemic cardiomyopathy as well.48 Ex vivo measures of skeletal myoblasts co-cultured with cardiomyocytes demonstrated transdifferentiation with formation of direct cell-to-cell signaling.49 The histologic and functional changes are similar to transplantation of bone marrow-derived progenitor cells.50
Preclinical data from rat models of autologous skeletal myoblast transplant into infarcted myocardium suggests that culture technique measurably impacts ventricular performance after transplant.51 Cryopreservation of harvested cells in a hamster model was not associated with decreased cell viability.52 Transplanted myoblasts, however, demonstrate formation of myofibers and markers of cell division that suggest viability after transfer in rat models.53 In canine models, implanted skeletal myoblasts were associated with induction of cellular hypertrophy of host myocytes at infarct sites.54 In other measures of ventricular remodeling, improvements in ventricular performance are additive to those observed with angiotensin converting enzyme inhibitor treatment.25 These effects remain durable for up to a year, with observed mechanisms of colonization of scar fibrosis by skeletal muscle cells thought to augment compliance.55 Other models of delivery include intracoronary infusion, which in preclinical canine models demonstrated a phenotype of striated muscle in infarct zones.56
3.2 Clinical Studies
From this basis, clinical studies have examined the efficacy of this cell type in improving ventricular function in chronic cardiomyopathy. In contrast to progenitor cell studies, here the cell identity and mode of harvest is better defined. Moreover, issues of timing are less pertinent when exploring cell therapy of chronic heart failure rather than acute myocardial infarction. As in therapeutic progenitor cell studies, investigators have sought to address issues of therapeutic dose and of cell delivery in trials of autologous skeletal myoblast therapy. Clinical benefits have likewise been modest, but observed salutary effects of skeletal myoblast therapy have encouraged continued study (though mindful of safety concerns from tachyarrhythmias).
Early clinical experience has provided anecdotes of successful cell engraftment in several case series using direct intramyocardial injection at the time of cardiac surgery. One subject transplanted with skeletal myoblasts at the time of coronary artery bypass grafting evinced long-term viability (17.5 months) and an interesting phenotypic change in the grafted cells to slow-twitch fibers.57 Another series of five subjects with end-stage ischemic cardiomyopathy transplanted with autologous skeletal myoblasts at the time of left ventricular assist device (LVAD) implantation found myoblast cell survival (mean 124 days), with alignment of myofibers with host myocardial fibers.58
Yield from muscle biopsy averages around 870 million cells arising at 2-3 weeks after quadriceps muscle biopsy. Among these, more than 70% are CD56-positive myoblasts with greater than 90% viability.59 Long-term survival, however, has been measured at less than 1% from a delivered dose of 300 × 106 cells.58
Larger studies have found improvements in left ventricular function associated with direct injection of autologous skeletal myoblasts. Menasche and co-workers implanted 10 subjects with advanced left ventricular dysfunction with 871 × 106 skeletal myoblasts in myocardial scar at the time of coronary artery bypass grafting.60 In this unblinded phase I study, investigators reported improvements in New York Heart Association functional class, improvement in global left ventricular ejection fraction, and improvement in regional ejection fraction in the majority of scar sites injected. Meanwhile, adverse events included sustained ventricular tachycardia in four subjects. A larger phase 2 study (MAGIC) randomized 97 subjects to autologous skeletal myoblast injection at the time of bypass surgery vs. placebo, finding no significant improvement in regional or global ventricular performance by echocardiography; however, left ventricular volumes improved relative to placebo therapy.61,62 A similar study of 10 subjects referred for coronary artery bypass grafting reported improvement in left ventricular ejection fraction at 4 months and 1 year after implant.63 Notably, culture yields (and thus doses) ranged from 400,000 to 50 million cells (65.4% myoblasts). Also, ventricular tachycardia was observed in five subjects.61 Dib and co-workers observed evidence of increase areas of myocardial viability by positron emission tomography scanning in 30 subjects treated with direct injection of autologous skeletal myoblasts at the time of coronary artery bypass surgery (n = 24) or LVAD implantation (n = 6).64,65
Alternative models of cell delivery include percutaneous endomyocardial injection with electromechanical mapping of the ventricle to identify areas of scar.66 A pilot study of five subjects with ischemic cardiomyopathy injected with a 296 ± 199 million skeletal myoblasts found improvement in global left ventricular ejection fraction and in regional wall motion by magnetic resonance imaging. One subject had an implantable cardioverter defibrillator placed for non unsustained ventricular tachycardia. At 1 year, functional class, contractile reserve, and end-systolic volumes improved.67 A subsequent case-controlled study of transcatheter transplant of autologous skeletal myoblasts demonstrated improvements in left ventricular ejection fraction, walking distance, and functional class.68 Cellular yield was 210 ± 150 million cells, implanted over an average of 19 ± 10 injection sites. Finally, skeletal myoblasts have been implanted via injection across the coronary sinus in 10 subjects with ischemic cardiomyopathy, resulting in up to 100 million cells injected and improvements in functional class.69
3.3 Limitations and Future Directions
In addition to modest improvements to date in blinded, placebo-controlled trials of autologous skeletal myoblasts for ischemic cardiomyopathy, the incidence of ventricular tachycardia with this therapy has raised safety concerns. Mechanisms of ventricular tachycardia in this setting has been attributed to several factors. The absence of gap junctions on skeletal muscle cells is thought to promote spiral waves conducive for reentrant ventricular tachycardia.70,71 Genetic modification of cells to increase expression of gap junction (i.e., connexion 43) has been a suggested method of decreasing arrhythmic risk.70,72–74 Presently, phase II/III multicenter studies are underway to evaluate the efficacy of skeletal myoblast therapy, with an implanted cardioverter-defibrillator as a prerequisite to study entry.
4 Mesenchymal Stem Cells - Allogeneic Mesenchymal Stem Cells
A population of nonhematopoietic pluripotent cells resident in the bone marrow that give rise to cardiomyocytes (as well as osteocytes, chondrocytes, and adipocytes) are known as mesenchymal stem cells (MSC).75,76 Given its propensity to form cardiomyocytes, this cell line has been the focus of work targeting left ventricular dysfunction. Interestingly, though expressing human leukocyte antigen major histocompatibility complex class I molecules, MSCs do not express co-stimulatory molecules and thus escape recognition by alloreactive T cells.77 As a result, they enjoy a relatively immune-privileged state, which allows for allogenic cell transplant as a mode of therapy.
Preclinical work has supported the concept that these immune-privileged bone marrow derived allogeneic cells could contribute to regeneration.78 Rat models of cryoinjured myocardium exhibited improvement in left ventricular function after direct injection of bone marrow-derived MSCs.78 Allogeneic MSC injected into the scar of a model of infarction in rats demonstrated transient improvement in ventricular performance, while expressing muscle-specific markers and long-term survival at 6 months.79 Another work in rat models has shown formation of clusters of cells on infarct border zones in addition to microvessel formation.80 Direct injection of infarcted myocardium in a swine model in the peri-infarct period with allogenic MSC resulted in persistent engraftment at 8 weeks, improvement in infarct size and tissue perfusion by magnetic resonance imaging, and improvements in hemodynamics.81–84 Short-term survival may improve in this model and cell type with adjunctive transmyocardial laser revascularization.85 The mechanism of these improvements, in addition to supposed direct differentiation into cardiomyocytes, contribution of paracrine signaling, and fusion with existing cardiac cells, has been supposed to include stimulation of stem cell niches resident in cardiac tissue.86 A phase I study of allogeneic MSC therapy administered intravenously after acute myocardial infarction has been completed with results forthcoming.
5 Resident Cardiac Stem Cells
A population of undifferentiated cells has been isolated from subcultures of postnatal atrial or ventricular human biopsy specimens and from mouse hearts, lending to the support of the existence of stem cells that reside within the adult heart.87–90 Growing in self-adherent clusters ex vivo, these “cardiospheres” are clonogenic, are capable of self-renewal, and can differentiate in vitro and in vivo into cells with myocardial and vascular phenotypes.
Preclinical work has uncovered that these cardiospheres in culture express endothelial markers (KDR or flk-1, CD31) and stem cell markers (CD34, c-kit, and Sca-1), as well as other proteins essential for contractile and electrical function.89 Cardiomyocyte differentiation transcription factors are upregulated in these cell colonies.91 These cells appear to migrate in vitro in response to cytokines elaborated by circulating EPCs.92 Functionally, cells derived from cardiospheres demonstrate electrical coupling in vitro.89 Moreover, when transplanted in a mouse model of myocardial infarction, they appear to yield the phenotype of cardiomyocytes, endothelial cells, and smooth muscle cells with improvements in ventricular performance and reduction in scar size.87,89 Notably, these effects were not observed with implanted fibroblasts, suggesting a possible role for these cells as an autologous source of regenerative tissue.
Presently, no human studies have been performed using resident cardiac stem cells in treating cardiovascular disease.
6 Human Embryonic Stem Cells
Ethical and practical concerns have limited the study of stem cells derived from human embryos in both preclinical and clinical settings.93 In vitro studies of human embryonic stem cells have demonstrated that cultivated aggregates termed embryoid bodies (EB) exhibit potential for developing into cardiomyocytes.73 Spontaneously contracting regions of EBs stain for elements of cardiac tissue (cardiac myosin heavy chain, alpha-actinin, desmin, troponin I, and atrial natriuretic peptide) show myofibrillar organization under electron microscopy, and electrical properties. Spontaneous contraction is reported in a percentage of EBs.73 Another model of cardiomyocyte differentiation from human embryonic stem cells involves co-culture with visceral-endoderm (VE)-like cells from mice, highlighting paracrine interactions between the endoderm in the development of cardiac cells.94,95 These cells in culture demonstrate coupling via gap junctions and functional calcium ion channels.94
Xue and co-workers demonstrated a model of human embryonic stem cell-derived cardiomyocytes that integrate into “recipient” cardiac tissue and demonstrate electrical and mechanical coupling in vitro and in vivo, supporting the possibility of cell-based pacemakers.96 Other investigators have shown in canine models the durability of human MSCs for cardiac pacing as long as 6 weeks after implantation, when dosed at >700,000 cells per injection.97 Laflamme and co-workers demonstrated that injection of differentiated cardiac-enriched human embryonic stem cells into athymic rats resulted in proliferation of cardiomyocytes with time, typified by angiogenesis and expression of cardiac markers.98 Understanding of the molecular mechanisms of differentiation of human embryonic stem cells remains rudimentary, but work by Singh and colleagues suggests that the nuclear protein Chibby facilitates cardiac cell development.99 Notably, embryonic stem cell-derived cardiomyocytes implanted in infarcted cardiac tissue resulted in attenuation of scar thinning, improvements in left ventricular dilatation, wall motion score index, and left ventricular diastolic dimensions.100,101
In addition to ethical and logistical issues related to the use of human embryonic stem cells in studies or therapies of cardiovascular disease, further concerns about aberrant development have been raised when undifferentiated human embryonic stem cells and human EB injected into normal rat myocardium resulted in teratoma formation.100,101
7 Technical Considerations
As with pharmaceutical therapy for common cardiovascular conditions, the clinical outcome in cell therapy is in part informed by the dose, the potency, and the mechanism of effect.2,102 Preparation of cell product can reduce the number and robustness of available cells. Several studies have sought to establish a dose-response relationship to therapy, but the adequate dosing of cell-based therapies remains largely empiric. It is estimated that a typical myocardial infarction results in loss of a billion cardiomyocytes, while most trials have isolated and transplanted a dose on the order of 10 to 100 million cells. On delivery, cells are subjected to migration away from the target site, acute oxidative stress, ischemia, and inflammation.102 Moreover, determining an effect attributable to injected cells must be separated from improvements due to the passive effects of injected biomaterials.103 Addressing the concern that the extracellular matrix may be perturbed and thus contribute to the pathophysiology of chronic ischemic cardiomyopathy, recent work has employed a cell-seeded collagen matrix implanted in subjects undergoing coronary artery bypass surgery - finding increases in infarct scar and improvements in global ejection fraction.104 Additionally, application of a fibrin glue has been shown to be beneficial with regard to cell transplant survival, infarct size reduction, and blood flow restoration.105
8 Conclusions
Advances in stem cell biology over the past decade have fuelled interest in new therapies for acute and chronic cardiovascular diseases. Preclinical work with a variety of cell types has suggested efficacy in improving ischemia and ventricular function, although mechanisms of effect remain to be fully explained. Human studies using certain cell types have shown modest clinical efficacy, while the safety of these experimental therapies supports continuing patient-oriented research.
References
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Murrow, J.R., Dhawan, S.S., Quyyumi, A.A. (2009). Cell Therapy for Cardiovascular Disease. In: Abraham, D., Clive, H., Dashwood, M., Coghlan, G. (eds) Advances in Vascular Medicine. Springer, London. https://doi.org/10.1007/978-1-84882-637-3_8
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