Cell-Based Therapy for Myocardial Ischemia and Infarction: Pathophysiological Mechanisms

Laflamme, Michael A.; Zbinden, Stephan; Epstein, Stephen E.; Murry, Charles E.

doi:10.1146/annurev.pathol.2.010506.092038

Cited by 154 publications

(161 citation statements)

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“…Many strategies being pursued to restore heart function involve repopulating the heart with exogenously delivered cells, either by direct injection [1,2] or intravascular delivery. The first attempts to repopulate the scarred aftermath of myocardial infarction (MI) were performed over fifteen years ago [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…The first attempts to repopulate the scarred aftermath of myocardial infarction (MI) were performed over fifteen years ago [3][4][5]. Since that time, interest in cell transplantation for the prevention and treatment of heart failure has exploded, leading to multiple animal studies and clinical trials [2]. These studies showed that a panoply of cells injected into the myocardium both can change the nature of the scar and improve post-infarction cardiac function.…”

Section: Introductionmentioning

confidence: 99%

“…Several human clinical trials testing cell-based cardiac repair have been conducted, the progress of which has been reviewed elsewhere [2,28]. Despite the promising preclinical benefits of cell therapy, success in these initial clinical trials has been modest, at best.…”

Section: Introductionmentioning

confidence: 99%

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Systems approaches to preventing transplanted cell death in cardiac repair

Robey

Saiget

Reinecke

et al. 2008

Journal of Molecular and Cellular Cardiology

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294

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Stem cell transplantation may repair the injured heart, but tissue regeneration is limited by death of transplanted cells. Most cell death occurs in the first few days post-transplantation, likely from a combination of ischemia, anoikis and inflammation. Interventions known to enhance transplanted cell survival include heat shock, over-expressing anti-apoptotic proteins, free radical scavengers, anti-inflammatory therapy and co-delivery of extracellular matrix molecules. Combinatorial use of such interventions markedly enhances graft cell survival, but death still remains a significant problem. We review these challenges to cardiac cell transplantation and present an approach to systematically address them.Most anti-death studies use histology to assess engraftment, which is time-and labor-intensive. To increase throughput, we developed two biochemical approaches to follow graft viability in the mouse heart. The first relies on LacZ enyzmatic activity to track genetically modified cells, and the second quantifies human genomic DNA content using repetitive Alu sequences. Both show linear relationships between input cell number and biochemical signal, but require correction for the time lag between cell death and loss of signal. Once optimized, they permit detection of as few as 1 graft cell in 40,000 host cells. Pro-survival effects measured biochemically at three days predict long-term histological engraftment benefits. These methods permitted identification of carbamylated erythropoietin (CEPO) as a pro-survival factor for human embryonic stem cell-derived cardiomyocyte grafts. CEPO's effects were additive to heat shock, implying independent survival pathways. This system should permit combinatorial approaches to enhance graft viability in a fraction of the time required for conventional histology.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Systems approaches to preventing transplanted cell death in cardiac repair

Robey

Saiget

Reinecke

et al. 2008

Journal of Molecular and Cellular Cardiology

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364

294

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“…Several approaches to increase the number of CMs within injured myocardium have been attempted, including (1) activation and stimulation of host myocardial regeneration by transplanted cells via angiogenic and=or paracrine effects, 4,5 (2) direct transplantation of functional CMs or myogenic cells, [6][7][8] and (3) implantation of tissue constructs containing CMs. 9,10 In the latter two cases, the ideal donor CMs possess a high potential for division during cell preparation and potential for further proliferation following implantation to form a viable myocardial tissue within the surrounding injured recipient myocardium.…”

Section: Introductionmentioning

confidence: 99%

Engineered Early Embryonic Cardiac Tissue Increases Cardiomyocyte Proliferation by Cyclic Mechanical Stretch via p38-MAP Kinase Phosphorylation

Clause

Tinney

Liu

et al. 2009

Tissue Engineering Part A

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Cardiomyocyte (CM) transplantation is one therapeutic option for cardiac repair. Studies suggest that fetal CMs display the best cell type for cardiac repair, which can finitely proliferate, integrate with injured host myocardium, and restore cardiac function. We have recently developed an engineered early embryonic cardiac tissue (EEECT) using embryonic cardiac cells and have shown that EEECT contractile properties and cellular proliferative response to cyclic mechanical stretch stimulation mimic developing fetal myocardium. However, it remains unknown whether cyclic mechanical stretch-mediated high cellular proliferation activity within EEECT reflects CM or non-CM population. Studies have shown that p38-mitogen-activated protein kinase (p38MAPK) plays an important role in both cyclic mechanical stretch stimulation and cellular proliferation. Therefore, in the present study, we tested the hypothesis that cyclic mechanical stretch (0.5 Hz, 5% strain for 48 h) specifically increases EEECT CM proliferation mediated by p38MAPK activity. Cyclic mechanical stretch increased CM, but not non-CM, proliferation and increased p38MAPK phosphorylation. Treatment of EEECT with the p38MAPK inhibitor, SB202190, reduced CM proliferation. The negative CM proliferation effects of SB202190 were not reversed by concurrent stretch stimulation. Results suggest that immature CM proliferation within EEECT can be positively regulated by mechanical stretch and negatively regulated by p38MAPK inhibition.

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“…relative abundance | lipid-mediated | TIPeR | microarray | patch clamp C ardiomyocytes are among the most sought-after cells in regenerative medicine because they may help to repair an injured heart by replacing lost tissue (1,2). Functional cardiomyocyte-like cells have been induced from embryonic stem cells (ESCs), induced from pluripotent stem cells (iPSCs), and generated from direct conversion of fibroblasts using defined transcription factor transduction (3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

Transcriptome transfer provides a model for understanding the phenotype of cardiomyocytes

Kim¹,

Sul²,

Peternko

et al. 2011

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

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We show that the transfer of the adult ventricular myocyte (AVM) transcriptome into either a fibroblast or an astrocyte converts the host cell into a cardiomyocyte. Transcriptome-effected cardiomyocytes (tCardiomyocytes) display morphologies, immunocytochemical properties, and expression profiles of postnatal cardiomyocytes. Cell morphology analysis shows that tCardiomyoctes are elongated and have a similar length-to-width ratio as AVMs. These global phenotypic changes occur in a time-dependent manner and confer electroexcitability to the tCardiomyocytes. tCardiomyocyte generation does not require continuous overexpression of specific transcription factors; for example, the expression level of transcription factor Mef2c is higher in tCardiomyocytes than in fibroblasts, but similar in tCardiomyocytes and AVMs. These data highlight the dominant role of the gene expression profile in developing and maintaining cellular phenotype. The transcriptomeinduced phenotype remodeling-generated tCardiomyocyte has significant implications for understanding and modulating cardiac disease development.C ardiomyocytes are among the most sought-after cells in regenerative medicine because they may help to repair an injured heart by replacing lost tissue (1, 2). Functional cardiomyocyte-like cells have been induced from embryonic stem cells (ESCs), induced from pluripotent stem cells (iPSCs), and generated from direct conversion of fibroblasts using defined transcription factor transduction (3-7). ESC-derived and iPSCderived cardiomyocytes exhibit many characteristics of cardiomyocytes, including electric activity, contractile movement, and up-regulation of cardiac genes; however, both stem cellderived cardiomyocytes are mixed populations of atrial, ventricular, and other cells, limiting their use in research and clinical application. In addition to heterogeneity of the cells, stem cellderived cardiomyocytes remain embryonic cardiomyocytes even after 2 mo under standard 2D culture conditions (5, 6). Transcription factor-induced cardiomyocytes also have many characteristics of neonatal cardiomyocytes (4). Furthermore, carcinogenesis and early senescence often develop in transcription factor-mediated induction of such phenotypic changes (8, 9).We have previously shown that the transfer of transcriptome (TIPeR) from a rat astrocyte into a rat neuron converts the electrically active neuron into an electrically quiescent tAstrocyte cell (10). We asked whether the change in expression profile (i.e., modulation of relative abundance of gene products) could transdifferentiate electrically quiescent cells into electrically excitable cells. Here we demonstrate the conversion of an electrically quiescent fibroblast directly into an electrically excitable tCardiomyocyte in a mouse system. We also show that another electrically quiescent cell, the astrocyte, can be converted into a tCardiomyocyte. This conversion was confirmed by a diverse set of single-cell phenotyping procedures. Results Generation of tCardiomyocytes from Fibroblasts by Trans...

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Cell-Based Therapy for Myocardial Ischemia and Infarction: Pathophysiological Mechanisms

Cited by 154 publications

References 154 publications

Systems approaches to preventing transplanted cell death in cardiac repair

Systems approaches to preventing transplanted cell death in cardiac repair

Engineered Early Embryonic Cardiac Tissue Increases Cardiomyocyte Proliferation by Cyclic Mechanical Stretch via p38-MAP Kinase Phosphorylation

Transcriptome transfer provides a model for understanding the phenotype of cardiomyocytes

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