Concise Review: The Role of Clinical Trials in Deciphering Mechanisms of Action of Cardiac Cell-Based Therapy

Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.
STEM CELLS TRANSLATIONAL MEDICINE (Impact Factor: 5.71). 11/2012; 1(1):29-35. DOI: 10.5966/sctm.2011-0014
Source: PubMed


Although the initial promise of cardiac cell-based therapy was based on the concept that stem cells engraft into diseased tissue and differentiate into beating cardiomyocytes, it is now clear that successful cell-based tissue repair involves a more complex orchestration of cellular and molecular events. Many lessons about successful tissue repair can be gleaned from the results of early-stage clinical trials. This body of work shows that cell-based therapy (with various cell sources and delivery methods) effectively prevents and reverses the remodeling process, the sine qua non of the myocardial injury reaction and anatomic substrate for subsequent clinical events. The potentially favorable remodeling responses to cell therapy have prompted a search for mechanisms of action beyond cell repopulation and guided future clinical trial design by providing more clear focus on pathophysiological endpoints signifying favorable responses to cell-based therapy. Perhaps the most important mechanistic insight is that endogenous stem/precursor cells have the potential to participate in tissue healing. With regard to the phenotype of cellular response, it is clear that parameters of remodeling, such as infarct size and ventricular dimensions, should be directly measured, thereby necessitating the use of sophisticated imaging modalities, such as cardiac magnetic resonance imaging or multidetector computed tomography. These new insights offer an optimistic outlook on the state of cell-based therapeutics for cardiac disease and suggest that pivotal clinical trials are warranted. Here, we review lessons learned from clinical trials and evaluate the choice and assessment of endpoints to best predict efficacy of cell therapy.

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    • "In the past decade, heart disease has become the leading cause of death worldwide and has continued to be a major economic burden to developed countries [1]. However, recent research suggests that stem cells may be the key to understanding, treating, and even reversing heart disease [2] [3]. Investigators have used human cardiomyocytes derived from stem cells (hSC-CMs) as a model system to study the developmental and pathological states of the heart at the cellular level [4] [5] [6] [7] [8]. "
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    ABSTRACT: Human stem cell-derived cardiomyocytes hold promise for heart repair, disease modeling, drug screens and questions of fundamental biology. All of these applications can be improved by assessing the contractility of cardiomyocytes at the single-cell level. We have developed an in vitro platform for assessing the contractile performance of stem cell-derived cardiomyocytes that is compatible with other common endpoints such as microscopy and molecular biology. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were seeded onto elastomeric micropost arrays in order to characterize the contractile force, velocity, and power produced by these cells. We assessed contractile function by tracking the deflection of all of the microposts underneath an individual hiPSC-CM with optical microscopy. Immunofluorescent staining of these cells was used with the microposts to assess their spread area, nucleation, and sarcomeric structure. Following seeding of hiPSC-CMs onto microposts coated with fibronectin, laminin, and collagen IV, we found that hiPSC-CMs on laminin coatings demonstrated higher attachment, spread area, and contractile force than those seeded on fibronectin or collagen IV coatings. Under optimized conditions, hiPSC-CMs spread to an area of approximately 420 square microns, generated total systolic force of 15 nanonewtons per cell, showed contraction and relaxation rates of 6.5 microns per second and 5.25 microns per second, respectively, and had a peak upstroke power of 29 femtowatts. Thus, elastomeric micropost arrays can be used to study the contractile strength and kinetics of hiPSC-CMs. This system should facilitate studies of hiPSC-CM maturation, disease modeling and drug screens as well as fundamental studies of human cardiac contraction.
    Journal of Biomechanical Engineering 03/2014; 136(5). DOI:10.1115/1.4027145 · 1.78 Impact Factor
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    • "However, the results suggest that it is not that simple and that the modest improvements seen are probably due to the exogenous cells creating a permissible environment (by secreting factors and appropriate signals) that induces the endogenous cardiomyocytes or cardiac stem cells to proliferate. It is therefore suggested that basic knowledge of stem cell and developmental biology be exploited to further increase the positive effects seen thus far.30 "
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    ABSTRACT: The human heart is the first organ to develop and its development is fairly well characterised. In theory, the heart has the capacity to regenerate, as its cardiomyocytes may be capable of cell division and the adult heart contains a cardiac stem cell niche, presumably capable of differentiating into cardiomyocytes and other cardiac-associated cell types. However, as with most other organs, these mechanisms are not activated upon serious injury. Several experimental options to induce regeneration of the damaged heart tissue are available: activate the endogenous cardiomyocytes to divide, coax the endogenous population of stem cells to divide and differentiate, or add exogenous cell-based therapy to replace the lost cardiac tissue. This review is a summary of the recent research into all these avenues, discussing the reasons for the limited successes of clinical trials using stem cells after cardiac injury and explaining new advances in basic science. It concludes with a reiteration that chances of successful regeneration would be improved by understanding and implementing the basics of heart development and stem cell biology.
    06/2013; 24(5):189-93. DOI:10.5830/CVJA-2013-045
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    ABSTRACT: Whereas cardiac-derived c-kit(+) stem cells (CSCs) and bone marrow-derived mesenchymal stem cells (MSCs) are undergoing clinical trials testing safety and efficacy as a cell-based therapy, the relative therapeutic and biologic efficacy of these two cell types is unknown. We hypothesized that human CSCs have greater ability than MSCs to engraft, differentiate, and improve cardiac function. We compared intramyocardial injection of human fetal CSCs (36,000) with two doses of adult MSCs (36,000 and 1,000,000) or control (phosphate buffered saline) in nonobese diabetic/severe combined immune deficiency mice after coronary artery ligation. The myocardial infarction-induced enlargement in left ventricular chamber dimensions was ameliorated by CSCs (p < .05 for diastolic and systolic volumes), as was the decline in ejection fraction (EF; p < .05). Whereas 1 × 10(6) MSCs partially ameliorated ventricular remodeling and improved EF to a similar degree as CSCs, 36,000 MSCs did not influence chamber architecture or function. All cell therapies improved myocardial contractility, but CSCs preferentially reduced scar size and reduced vascular afterload. Engraftment and trilineage differentiation was substantially greater with CSCs than with MSCs. Adult-cultured c-kit(+)CSCs were less effective than fetal, but were still more potent than high-dose MSCs. These data demonstrate enhanced CSC engraftment, differentiation, and improved cardiac remodeling and function in ischemic heart failure. MSCs required a 30-fold greater dose than CSCs to improve cardiac function and anatomy. Together, these findings demonstrate a greater potency of CSCs than bone marrow MSCs in cardiac repair.
    STEM CELLS TRANSLATIONAL MEDICINE 02/2012; 1(2):116-24. DOI:10.5966/sctm.2011-0015 · 5.71 Impact Factor
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