Cardiac Differentiation of Human Embryonic Stem Cells and their Assembly into Engineered Heart Muscle

Soong, Poh Loong; Tiburcy, Malte; Zimmermann, Wolfram‐Hubertus

doi:10.1002/0471143030.cb2308s55

Cited by 39 publications

(36 citation statements)

References 47 publications

(67 reference statements)

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“…However, we observed higher calcium sensitivity and slower contraction kinetics in the EHM. This is not a peculiar observation in EHM generated from PSCs, but a general finding also in EHM from neonatal rodent cardiomyocytes (49), as well as mouse and human ESC-and iPSC-derived myocytes (50,51). Whether limited diffusibility or fundamental differences in calcium handling account for this finding remains to be clarified.…”

Section: Discussionmentioning

confidence: 73%

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Parthenogenetic stem cells for tissue-engineered heart repair

Didié¹,

Christalla²,

Rubart³

et al. 2013

J. Clin. Invest.

101

112

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Uniparental parthenotes are considered an unwanted byproduct of in vitro fertilization. In utero parthenote development is severely compromised by defective organogenesis and in particular by defective cardiogenesis. Although developmentally compromised, apparently pluripotent stem cells can be derived from parthenogenetic blastocysts. Here we hypothesized that nonembryonic parthenogenetic stem cells (PSCs) can be directed toward the cardiac lineage and applied to tissue-engineered heart repair. We first confirmed similar fundamental properties in murine PSCs and embryonic stem cells (ESCs), despite notable differences in genetic (allelic variability) and epigenetic (differential imprinting) characteristics. Haploidentity of major histocompatibility complexes (MHCs) in PSCs is particularly attractive for allogeneic cell-based therapies. Accordingly, we confirmed acceptance of PSCs in MHC-matched allotransplantation. Cardiomyocyte derivation from PSCs and ESCs was equally effective. The use of cardiomyocyte-restricted GFP enabled cell sorting and documentation of advanced structural and functional maturation in vitro and in vivo. This included seamless electrical integration of PSC-derived cardiomyocytes into recipient myocardium. Finally, we enriched cardiomyocytes to facilitate engineering of force-generating myocardium and demonstrated the utility of this technique in enhancing regional myocardial function after myocardial infarction. Collectively, our data demonstrate pluripotency, with unrestricted cardiogenicity in PSCs, and introduce this unique cell type as an attractive source for tissue-engineered heart repair.

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Section: Discussionmentioning

confidence: 73%

“…we assume that they will be amenable to myocardial tissue engineering just as human ESC and iPSCs are (50,51).…”

Section: Figurementioning

confidence: 99%

Parthenogenetic stem cells for tissue-engineered heart repair

Didié¹,

Christalla²,

Rubart³

et al. 2013

J. Clin. Invest.

101

112

View full text Add to dashboard Cite

show abstract

“…Using differentiated cardiac cells derived from H9, HES3 and HES3 NKX2-5 eGFP/w cell lines, hCOs were formed using previously described bioengineering approaches (Zimmermann et al, 2002;Tiburcy et al, 2014;Soong et al, 2012). Briefly, cardiac cells were cast in circular wells (Fig.…”

Section: Results Hcos Possess Features Of Immature Human Myocardiummentioning

confidence: 99%

Development of a human cardiac organoid injury model reveals innate regenerative potential

et al. 2017

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The adult human heart possesses a limited regenerative potential following an ischemic event, and undergoes a number of pathological changes in response to injury. While cardiac regeneration has been documented in zebrafish and neonatal mouse hearts, it is currently unknown whether the immature human heart is capable of undergoing complete regeneration. Combined progress in pluripotent stem cell differentiation and tissue engineering has facilitated the development of human cardiac organoids (hCO), which resemble fetal heart tissue and can be used to address this important knowledge gap. This study aimed to characterise the regenerative capacity of immature human heart tissue in response to injury. Following cryoinjury with a dry ice probe, hCO exhibited an endogenous regenerative response with full functional recovery by two weeks following acute injury. Cardiac functional recovery occurred in the absence of pathological fibrosis or cardiomyocyte hypertrophy. Consistent with regenerative organisms and neonatal human hearts, there was a high basal level of cardiomyocyte proliferation, which may be responsible for the regenerative capacity of the hCO. This study suggests that immature human heart tissue has an intrinsic capacity to regenerate.

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“…A great effort is currently underway to promote the maturation of embryo-derived stem cells by a multitude of methods, including manipulation of growth factors 19 , electrical stimulation 20 and mechanical stretching 21 . To date, monitoring the developmental stages of human embryonic stem cell (hESC)-derived cardiomyocytes (hESC-CM) has been dependent on gene expression levels and morphological changes 22 .…”

Section: Resultsmentioning

confidence: 99%

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

et al. 2015

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Membrane proteins are crucial to heart function and development. Here we combine cationic silica-bead coating with shotgun proteomics to enrich for and identify plasma membrane-associated proteins from primary mouse neonatal and human fetal ventricular cardiomyocytes. We identify Tmem65 as a cardiac-enriched, intercalated disc protein that increases during development in both mouse and human hearts. Functional analysis of Tmem65 both in vitro using lentiviral shRNA-mediated knockdown in mouse cardiomyocytes and in vivo using morpholino-based knockdown in zebrafish show marked alterations in gap junction function and cardiac morphology. Molecular analyses suggest that Tmem65 interaction with connexin 43 (Cx43) is required for correct localization of Cx43 to the intercalated disc, since Tmem65 deletion results in marked internalization of Cx43, a shorter half-life through increased degradation, and loss of Cx43 function. Our data demonstrate that the membrane protein Tmem65 is an intercalated disc protein that interacts with and functionally regulates ventricular Cx43.

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Cardiac Differentiation of Human Embryonic Stem Cells and their Assembly into Engineered Heart Muscle

Cited by 39 publications

References 47 publications

Parthenogenetic stem cells for tissue-engineered heart repair

Parthenogenetic stem cells for tissue-engineered heart repair

Development of a human cardiac organoid injury model reveals innate regenerative potential

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

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