Human embryonic stem cell-derived cardiomyocytes engraft but do not alter cardiac remodeling after chronic infarction in rats

Fernandes, Sarah; Naumova, Anna V.; Zhu, Wei-Zhong; Laflamme, Michael A.; Gold, Joseph; Murry, Charles E.

doi:10.1016/j.yjmcc.2010.09.008

Cited by 151 publications

(147 citation statements)

References 29 publications

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“…Another significant challenge to clinical application relates to the fate of the hESC-derived cardiac cells upon transplantation (12). Several investigators have reported engraftment of hESCderived cells in infarcted mouse, rat, guinea pig, and pig hearts (14,33,34). Aside from the recent report of electromechanical integration of hESC-derived cardiomyocytes into guinea pig hearts, careful examination of animal models has revealed that the transplanted cells form islands of nascent myocardium within the scar zone (12).…”

Section: Discussionmentioning

confidence: 99%

Prospective isolation of human embryonic stem cell-derived cardiovascular progenitors that integrate into human fetal heart tissue

Ardehali

Ali

Inlay

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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A goal of regenerative medicine is to identify cardiovascular progenitors from human ES cells (hESCs) that can functionally integrate into the human heart. Previous studies to evaluate the developmental potential of candidate hESC-derived progenitors have delivered these cells into murine and porcine cardiac tissue, with inconclusive evidence regarding the capacity of these human cells to physiologically engraft in xenotransplantation assays. Further, the potential of hESC-derived cardiovascular lineage cells to functionally couple to human myocardium remains untested and unknown. Here, we have prospectively identified a population of hESC-derived ROR2 + / CD13 + /KDR + /PDGFRα + cells that give rise to cardiomyocytes, endothelial cells, and vascular smooth muscle cells in vitro at a clonal level. We observed rare clusters of ROR2 + cells and diffuse expression of KDR and PDGFRα in first-trimester human fetal hearts. We then developed an in vivo transplantation model by transplanting second-trimester human fetal heart tissues s.c. into the ear pinna of a SCID mouse. ROR2 + /CD13 + /KDR + /PDGFRα + cells were delivered into these functioning fetal heart tissues: in contrast to traditional murine heart models for cell transplantation, we show structural and functional integration of hESC-derived cardiovascular progenitors into human heart. engraftment | surface markers | Stem cells | mature cardiomyocytes | clonal analysis

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Section: Discussionmentioning

confidence: 99%

Prospective isolation of human embryonic stem cell-derived cardiovascular progenitors that integrate into human fetal heart tissue

Ardehali

Ali

Inlay

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Cell therapy represents a promising strategy to halt or reverse the progression of this disease, and a number of candidate cell types have been investigated in both preclinical and clinical studies with mixed success [1][2][3][4]. Pluripotent stem cell-derived cardiomyocytes (PSC-CMs), including human embryonic stem cell (hESC)-derived-and human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), offer a number of advantages for cell-based cardiac repair, but most in vivo studies as of yet have shown only partial or transient restoration of contractile function [5][6][7][8]. One potential explanation is the underdeveloped contractile properties of PSC-CMs, which lack the robust contractile machinery found in mature adult CMs and instead resemble primitive CMs [9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Structural and Functional Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells

Lundy

Zhu

Regnier

et al. 2013

Stem Cells and Development

624

674

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Despite preclinical studies demonstrating the functional benefit of transplanting human pluripotent stem cellderived cardiomyocytes (PSC-CMs) into damaged myocardium, the ability of these immature cells to adopt a more adult-like cardiomyocyte (CM) phenotype remains uncertain. To address this issue, we tested the hypothesis that prolonged in vitro culture of human embryonic stem cell (hESC)-and human induced pluripotent stem cell (hiPSC)-derived CMs would result in the maturation of their structural and contractile properties to a more adult-like phenotype. Compared to their early-stage counterparts (PSC-CMs after 20-40 days of in vitro differentiation and culture), late-stage hESC-CMs and hiPSC-CMs (80-120 days) showed dramatic differences in morphology, including increased cell size and anisotropy, greater myofibril density and alignment, sarcomeres visible by bright-field microscopy, and a 10-fold increase in the fraction of multinucleated CMs. Ultrastructural analysis confirmed improvements in the myofibrillar density, alignment, and morphology. We measured the contractile performance of late-stage hESC-CMs and hiPSC-CMs and noted a doubling in shortening magnitude with slowed contraction kinetics compared to the early-stage cells. We then examined changes in the calciumhandling properties of these matured CMs and found an increase in calcium release and reuptake rates with no change in the maximum amplitude. Finally, we performed electrophysiological assessments in hESC-CMs and found that late-stage myocytes have hyperpolarized maximum diastolic potentials, increased action potential amplitudes, and faster upstroke velocities. To correlate these functional changes with gene expression, we performed qPCR and found a robust induction of the key cardiac structural markers, including b-myosin heavy chain and connexin-43, in late-stage hESC-CMs and hiPSC-CMs. These findings suggest that PSC-CMs are capable of slowly maturing to more closely resemble the phenotype of adult CMs and may eventually possess the potential to regenerate the lost myocardium with robust de novo force-producing tissue.

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“…Our laboratory, as well as several others, has found that the inflammatory environment present at the site of injury can both positively and negatively affect the outcomes of tissue-engineered heart repair [Laflamme et al, 2007;van Laake et al, 2008;Fernandes et al, 2010]. Notably, cell implantation in the setting of acute cardiac infarction gives better therapeutic outcomes compared to chronic cardiac infarction, suggesting that the inflammatory response and the presence of macrophages do not necessarily limit the repair processes.…”

Section: Introductionmentioning

confidence: 83%

Optimizing Dynamic Interactions between a Cardiac Patch and Inflammatory Host Cells

Freytes

Santambrogio

Vunjak-Novakovic

2011

Cells Tissues Organs

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gineering modalities for cardiac repair, the host environment into which the repair cells are placed is largely overlooked. Within seconds of myocardial ischemia, hypoxia sets in in the myocardium and the inflammatory response starts, characterized by rapid deployment of circulating cells and the release of paracrine and autocrine signals. Therefore, the inflammatory conditions under which these interactions take place, the design of the scaffold material used, and the maturity of the implanted cells will determine the outcomes of any stem cell-based therapy. We discuss here the interactions between implanted and inflammatory cells of the host, which are critical for the design of effective heart repair therapies. AbstractDamaged heart muscle has only a minimal ability for regeneration following myocardial infarction in which cardiomyocytes are lost to ischemia. The most clinically promising approach to regeneration of cardiac muscle currently under investigation is that of injecting cardiogenic repair cells or implanting a preformed tissue-engineered patch. While major advances are being made in the derivation of functional human cardiomyocytes and the development of tissue-en-

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Human embryonic stem cell-derived cardiomyocytes engraft but do not alter cardiac remodeling after chronic infarction in rats

Cited by 151 publications

References 29 publications

Prospective isolation of human embryonic stem cell-derived cardiovascular progenitors that integrate into human fetal heart tissue

Prospective isolation of human embryonic stem cell-derived cardiovascular progenitors that integrate into human fetal heart tissue

Structural and Functional Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells

Optimizing Dynamic Interactions between a Cardiac Patch and Inflammatory Host Cells

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