How to make a cardiomyocyte

Später, Daniela; Hansson, Emil M.; Zangi, Lior; Chien, Kenneth R.

doi:10.1242/dev.091538

Cited by 129 publications

(124 citation statements)

References 204 publications

(214 reference statements)

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“…Thus, methods to generate induced cardiac-like myocytes (iCMs) by reprogramming fibroblasts with combinations of cardiac transcription factors represent a potential approach for enhancing cardiac repair (2)(3)(4)(5)(6)(7)(8). Various mixtures of proteins, microRNAs, and small molecules have been shown to activate cardiac gene expression in fibroblasts (9), confirming original observations made merely 5 y ago (2).…”

mentioning

confidence: 57%

Akt1/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes

Zhou

Dickson

Kim

et al. 2015

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

159

169

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Conversion of fibroblasts to functional cardiomyocytes represents a potential approach for restoring cardiac function after myocardial injury, but the technique thus far has been slow and inefficient. To improve the efficiency of reprogramming fibroblasts to cardiac-like myocytes (iCMs) by cardiac transcription factors [Gata4, Hand2, Mef2c, and Tbx5 (GHMT)], we screened 192 protein kinases and discovered that Akt/protein kinase B dramatically accelerates and amplifies this process in three different types of fibroblasts (mouse embryo, adult cardiac, and tail tip). Approximately 50% of reprogrammed mouse embryo fibroblasts displayed spontaneous beating after 3 wk of induction by Akt plus GHMT. Furthermore, addition of Akt1 to GHMT evoked a more mature cardiac phenotype for iCMs, as seen by enhanced polynucleation, cellular hypertrophy, gene expression, and metabolic reprogramming. Insulin-like growth factor 1 (IGF1) and phosphoinositol 3-kinase (PI3K) acted upstream of Akt whereas the mitochondrial target of rapamycin complex 1 (mTORC1) and forkhead box o3 (Foxo3a) acted downstream of Akt to influence fibroblast-to-cardiomyocyte reprogramming. These findings provide insights into the molecular basis of cardiac reprogramming and represent an important step toward further application of this technique.transdifferentiation | regeneration | cardiomyopathy | heart | cardiogenesis

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mentioning

confidence: 57%

Akt1/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes

Zhou

Dickson

Kim

et al. 2015

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

159

169

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“…Paraxial mesoderm subsequently buds off into tissue segments known as somites 4 , with dorsal somites (dermomyotome) giving rise to brown fat, skeletal muscle, and dorsal dermis, and ventral somites (sclerotome) yielding the bone and cartilage of the spine and ribs 5 . Separately, lateral mesoderm goes on to form limb bud mesoderm 6 and cardiac mesoderm 7 , the latter of which generates cardiomyocytes and other heart constituents.…”

Section: Background and Summarymentioning

confidence: 99%

An atlas of transcriptional, chromatin accessibility, and surface marker changes in human mesoderm development

et al. 2016

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Mesoderm is the developmental precursor to myriad human tissues including bone, heart, and skeletal muscle. Unravelling the molecular events through which these lineages become diversified from one another is integral to developmental biology and understanding changes in cellular fate. To this end, we developed an in vitro system to differentiate human pluripotent stem cells through primitive streak intermediates into paraxial mesoderm and its derivatives (somites, sclerotome, dermomyotome) and separately, into lateral mesoderm and its derivatives (cardiac mesoderm). Whole-population and single-cell analyses of these purified populations of human mesoderm lineages through RNA-seq, ATAC-seq, and high-throughput surface marker screens illustrated how transcriptional changes co-occur with changes in open chromatin and surface marker landscapes throughout human mesoderm development. This molecular atlas will facilitate study of human mesoderm development (which cannot be interrogated in vivo due to restrictions on human embryo studies) and provides a broad resource for the study of gene regulation in development at the single-cell level, knowledge that might one day be exploited for regenerative medicine.

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“…The differentiation of multi-potent mesodermal cells to a cardiac fate is orchestrated by various signaling events and the cardiac transcriptional program (for review see [32–34]). In this study we showed that Tbx20 is a critical component of the cardiac transcriptional program that drives the formation of cardiac progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

Tbx20 drives cardiac progenitor formation and cardiomyocyte proliferation in zebrafish

Lü

Langenbacher

Chen

2017

Developmental Biology

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Tbx20 is a T-box transcription factor that plays essential roles in the development and maintenance of the heart. Although it is expressed by cardiac progenitors in all species examined, an involvement of Tbx20 in cardiac progenitor formation in vertebrates has not been previously described. Here we report the identification of a zebrafish tbx20 mutation that results in an inactive, truncated protein lacking any functional domains. The cardiac progenitor population is strongly diminished in this mutant, leading to the formation of a small, stretched-out heart. We found that overexpression of Tbx20 results in an enlarged heart with significantly more cardiomyocytes. Interestingly, this increase in cell number is caused by both enhanced cardiac progenitor cell formation and the proliferation of differentiated cardiomyocytes, and is dependent upon the activity of Tbx20’s T-box and transcription activation domains. Together, our findings highlight a previously unappreciated role for Tbx20 in promoting cardiac progenitor formation in vertebrates and reveal a novel function for its activation domain in cardiac cell proliferation during embryogenesis.

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How to make a cardiomyocyte

Cited by 129 publications

References 204 publications

Akt1/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes

Akt1/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes

An atlas of transcriptional, chromatin accessibility, and surface marker changes in human mesoderm development

Tbx20 drives cardiac progenitor formation and cardiomyocyte proliferation in zebrafish

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