Mitotically Inactivated Embryonic Stem Cells Can Be Used as an In Vivo Feeder Layer to Nurse Damaged Myocardium after Acute Myocardial Infarction

Burt, Richard K.; Chen, You Hong; Verda, Larissa; Lucena, Carolina; Navale, Shankararao; Johnson, J.; Han, Xiaoqiang; Lomasney, Jon W.; Baker, Jessa M.; Ngai, Ka Leung; Kino, Aya; Carr, James C.; Kajstura, Jan; Anversa, Piero

doi:10.1161/circresaha.111.262584

Cited by 28 publications

(16 citation statements)

References 41 publications

(47 reference statements)

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“…Burt et al showed that mitotically inactivated ESCs improve cardiac function although do not survive long-term, thus circumventing adverse effects such as tumour formation [55]. The proposed mode of action was transient function as an in vivo feeder layer that nurses damaged myocardium.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Cell Therapies for the Treatment of Acute Myocardial Infarction: A Meta-Analysis from Mouse Studies

Lang

Wolfien

Langenbach

et al. 2017

Cell Physiol Biochem

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Aims: Stem cell-based regenerative therapies for the treatment of ischemic myocardium are currently a subject of intensive investigation. A variety of cell populations have been demonstrated to be safe and to exert some positive effects in human Phase I and II clinical trials, however conclusive evidence of efficacy is still lacking. While the relevance of animal models for appropriate pre-clinical safety and efficacy testing with regard to application in Phase III studies continues to increase, concerns have been expressed regarding the validity of the mouse model to predict clinical results. Against the background that hundreds of preclinical studies have assessed the efficacy of numerous kinds of cell preparations - including pluripotent stem cells - for cardiac repair, we undertook a systematic re-evaluation of data from the mouse model, which initially paved the way for the first clinical trials in this field. Methods and Results: A systematic literature screen was performed to identify publications reporting results of cardiac stem cell therapies for the treatment of myocardial ischemia in the mouse model. Only peer-reviewed and placebo-controlled studies using magnet resonance imaging (MRI) for left ventricular ejection fraction (LVEF) assessment were included. Experimental data from 21 studies involving 583 animals demonstrate a significant improvement in LVEF of 8.59%+/- 2.36; p=.012 (95% CI, 3.7–13.8) compared with control animals. Conclusion: The mouse is a valid model to evaluate the efficacy of cell-based advanced therapies for the treatment of ischemic myocardial damage. Further studies are required to understand the mechanisms underlying stem cell based improvement of cardiac function after ischemia.

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Section: Discussionmentioning

confidence: 99%

Cardiac Cell Therapies for the Treatment of Acute Myocardial Infarction: A Meta-Analysis from Mouse Studies

Lang

Wolfien

Langenbach

et al. 2017

Cell Physiol Biochem

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“…Cellular replacement approaches hold great promise for the treatment of this disease. Embryonic stem cells (ESC) [2], [3], induced pluripotent stem cells (iPSC) [4], [5], parthenogenetic stem cells [6] and their cardiomyocyte (CM) derivatives [7]–[12], as well as cardiac precursor cells [13], [14] and autologous adult stem cells [15], [16], have been shown to exert beneficial effects on the function of the injured heart after transplantation. However, only contractile CM are capable of electromechanical coupling with the host heart tissue, thereby contributing to its pump function [9], [12], [17].…”

Section: Introductionmentioning

confidence: 99%

Bioluminescent Imaging of Genetically Selected Induced Pluripotent Stem Cell-Derived Cardiomyocytes after Transplantation into Infarcted Heart of Syngeneic Recipients

et al. 2014

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Cell loss after transplantation is a major limitation for cell replacement approaches in regenerative medicine. To assess the survival kinetics of induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) we generated transgenic murine iPSC lines which, in addition to CM-specific expression of puromycin N-acetyl-transferase and enhanced green fluorescent protein (EGFP), also constitutively express firefly luciferase (FLuc) for bioluminescence (BL) in vivo imaging. While undifferentiated iPSC lines generated by random integration of the transgene into the genome retained stable FLuc activity over many passages, the BL signal intensity was strongly decreased in purified iPS-CM compared to undifferentiated iPSC. Targeted integration of FLuc-expression cassette into the ROSA26 genomic locus using zinc finger nuclease (ZFN) technology strongly reduced transgene silencing in iPS-CM, leading to a several-fold higher BL compared to iPS-CM expressing FLuc from random genomic loci. To investigate the survival kinetics of iPS-CM in vivo, purified CM obtained from iPSC lines expressing FLuc from a random or the ROSA26 locus were transplanted into cryoinfarcted hearts of syngeneic mice. Engraftment of viable cells was monitored by BL imaging over 4 weeks. Transplanted iPS-CM were poorly retained in the myocardium independently of the cell line used. However, up to 8% of cells survived for 28 days at the site of injection, which was confirmed by immunohistological detection of EGFP-positive iPS-CM in the host tissue. Transplantation of iPS-CM did not affect the scar formation or capillary density in the periinfarct region of host myocardium. This report is the first to determine the survival kinetics of drug-selected iPS-CM in the infarcted heart using BL imaging and demonstrates that transgene silencing in the course of iPSC differentiation can be greatly reduced by employing genome editing technology. FLuc-expressing iPS-CM generated in this study will enable further studies to reduce their loss, increase long-term survival and functional integration upon transplantation.

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“…29 Recent advances have offered considerable insight into molecular biology, self-renewal, and differentiation cardiac stem cells, as well as phenotypic characteristics that are would be expected to offer clinical applications. [30][31][32][33][34][35][36][37] The potential use of stem cells in repairing injured myocardium and improving heart failure has raised considered excitement in patients, physicians, and researchers alike. 38 The field, however, is in infancy and faces considerable challenges in attaining its goal of repairing the damaged myocardium and restoring cardiac function in ischemic heart disease ( Table 1).…”

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confidence: 99%

Recent Developments in Cardiovascular Stem Cells

Madonna

Ferdinándy

Caterina

et al. 2014

Circulation Research

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45Human embryonic stem cells have been shown to differentiate to beating cardiomyocytes, SA nodal-like cells and mesodermal Recent Developments in Cardiovascular Research:The goal of "Recent Developments" is to provide a concise but comprehensive overview of new advances in cardiovascular research, which we hope will keep our readers abreast of recent scientific discoveries and facilitate discussion, interpretation, and integration of the findings. This will enable readers who are not experts in a particular field to grasp the significance and effect of work performed in other fields. It is our hope and expectation that these "Recent Development" articles will help readers to gain a broader awareness and a deeper understanding of the status of research across the vast landscape of cardiovascular research-The Editors. 50 Moreover, the use of induced pluripotent stem cell-derived cardiac myocytes for cardiac repair is hampered by their immature phenotype and the presence of epigenetic and genetic changes.24,51,52 Resident and bone marrow cells and cortical bone-derived cells are considered as potential sources for differentiation to cardiac myocytes but lacking compelling evidence for cardiac myogenesis and perhaps exerting their salutary biological effects through paracrine mechanisms. 19,29,[53][54][55][56][57][58] Equally exciting and challenging are the discovery and characterization of other CPCs that could give raise to various cardiac cells types, including smooth muscle cells, endothelial cells, and fibroblasts. [59][60][61][62][63] An important problem to overcome is the multiple comorbidities and their comedications of ischemic heart disease patients with heart failure that may affect cytoprotective signaling triggered by the different stem cell, as well as survival and differentiation properties of such stem cells in the injured tissue. [64][65][66] Clearly, the rapid face of discoveries is dazzling and a complete coverage of the recent developments in cardiovascular stem cells would be beyond the scope of this article. We regret that many valuable works were not covered in part or at all included in the present overview on Recent Developments. Clinical Trials In Human PatientsThe ClinicalTrials.gov lists >1000 clinical trials including >600 studies in the United States alone that tests effects of various stem cells in human patients (http://www.clinicaltrials. gov/). The list includes 71 including 38 active clinical trials in patients with heart failure using various stem cells, such as adipose-derived, mesenchymal, human embryonic, autologous CD133 + and CD34 + stem cells among the others.18,67-74Autologous skeletal myoblasts were probably the first cell type used to regenerate functional myocardium. It was tested initially in a rabbit model of myocardial cryoinjury, which showed incorporation of the injected myoblasts and improved myocardial performance. 75 Subsequent observational studies were followed by randomized clinical trials in human patients with heart failure injected with autologous skele...

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Mitotically Inactivated Embryonic Stem Cells Can Be Used as an In Vivo Feeder Layer to Nurse Damaged Myocardium after Acute Myocardial Infarction

Abstract: Expression of Concern This article has a related Expression of Concern: 10.1161/RES.0000000000000241 ( Circ Res . 2018; doi: 10.1161/RES.0000000000000241)

Cited by 28 publications

References 41 publications

Cardiac Cell Therapies for the Treatment of Acute Myocardial Infarction: A Meta-Analysis from Mouse Studies

Cardiac Cell Therapies for the Treatment of Acute Myocardial Infarction: A Meta-Analysis from Mouse Studies

Bioluminescent Imaging of Genetically Selected Induced Pluripotent Stem Cell-Derived Cardiomyocytes after Transplantation into Infarcted Heart of Syngeneic Recipients

Recent Developments in Cardiovascular Stem Cells

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