Defining the earliest step of cardiovascular progenitor specification during embryonic stem cell differentiation

Bondue, Antoine; Tännler, Simon; Chiapparo, Giuseppe; Chabab, Samira; Ramialison, Mirana; Paulissen, Catherine; Beck, Benjamin; Harvey, Richard P.; Blanpain, Cédric

doi:10.1083/jcb.201007063

Cited by 114 publications

(102 citation statements)

References 40 publications

(89 reference statements)

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“…Specifically, we chose MESP1 as a marker for early cardiac mesoderm, NKX2-5 and ISL1 as markers for cardiovascular progenitors, and HAND2, MYOCD, TBX5, GATA4 , and MEF2C as markers for more established cardiac lineages. MESP1 is a transcription factor necessary for the specification of multipotent cardiovascular progenitors and the expression of cardiovascular transcription factors (13). HAND2 is a transcription factor involved in heart development (14), whereas MYOCD is a transcriptional co-activator of Serum Response Factor (SRF), which interacts with TBX5 to promote cardiac gene expression (15).…”

Section: Resultsmentioning

confidence: 99%

Effect of Human Donor Cell Source on Differentiation and Function of Cardiac Induced Pluripotent Stem Cells

Sánchez-Freire

Lee

et al. 2014

Journal of the American College of Cardiology

116

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Background Human-induced pluripotent stem cells (iPSCs) are a potentially unlimited source for generation of cardiomyocytes (iPSC-CMs). However, current protocols for iPSC-CM derivation face a number of challenges, including variability in somatic cell sources and inconsistencies in cardiac differentiation efficiency. Objectives We aimed to assess the effect of epigenetic memory on differentiation and function of iPSC-CMs generated from somatic cell sources of cardiac versus non-cardiac origins. Methods Cardiac progenitor cells (CPCs) and skin fibroblasts from the same donors were reprogrammed into iPSCs and differentiated into iPSC-CMs via embryoid body and monolayer-based differentiation protocols. Results Differentiation efficiency was found to be higher in CPC-derived iPSC-CMs (CPC-iPSC-CMs) than in fibroblast-derived iPSC-CMs (Fib-iPSC-CMs). Gene expression analysis during cardiac differentiation demonstrated upregulation of cardiac transcription factors in CPC-iPSC-CMs, including NKX2-5, MESP1, ISL1, HAND2, MYOCD, MEF2C, and GATA4. Epigenetic assessment revealed higher methylation in the promoter region of NKX2-5 in Fib-iPSC-CMs compared to CPC-iPSC-CMs. Epigenetic differences were found to dissipate with increased cell passaging, and a battery of in vitro assays revealed no significant differences in their morphological and electrophysiological properties at early passage. Finally, cell delivery into small animal myocardial infarction (MI) model indicated that CPC-iPSC-CMs and Fib-iPSC-CMs possess comparable therapeutic capabilities in improving functional recovery in vivo. Conclusions This is the first study to compare differentiation of iPSC-CMs from human CPCs versus human fibroblasts from the same donors. We demonstrate that while epigenetic memory improves differentiation efficiency of cardiac versus non-cardiac somatic cell source in vitro, it does not contribute to improved functional outcome in vivo.

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Section: Resultsmentioning

confidence: 99%

Effect of Human Donor Cell Source on Differentiation and Function of Cardiac Induced Pluripotent Stem Cells

Sánchez-Freire

Lee

et al. 2014

Journal of the American College of Cardiology

116

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“…During embryogenesis, CPCs of both first and second heart fields reside in the cardiac crescent. Several studies have isolated CPCs from embryos and embryonic stem cells (ESCs) using transcription factor (TF)-based reporters like Mesp1, Isl1, and Nkx2.5, but a master regulator of the CPC state has not yet been identified (Bondue et al, 2011; Masino et al, 2004; Moretti et al, 2006). Cell surface markers including Cxcr4, Pdgfr-α, Flk1/KDR and SIRPA have been used to identify PSCs-derived CPCs.…”

Section: Introductionmentioning

confidence: 99%

Lineage Reprogramming of Fibroblasts into Proliferative Induced Cardiac Progenitor Cells by Defined Factors

et al. 2016

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Summary Several studies have reported reprogramming of fibroblasts to induced cardiomyocytes; however, reprogramming to proliferative induced cardiac progenitor cells (iCPCs) remains to be accomplished. Here we report that a combination of eleven or five cardiac factors along with canonical Wnt and JAK/STAT signaling reprogrammed adult cardiac, lung and tail-tip fibroblasts into iCPCs. The iCPCs were cardiac mesoderm-restricted progenitors, which could be extensively expanded while maintaining multipotency to differentiate into cardiomyocytes, smooth muscle cells and endothelial cells in vitro. Moreover, iCPCs injected into the cardiac crescent of mouse embryos differentiated into cardiomyocytes. iCPCs transplanted into the post-myocardial infarction mouse heart improved survival and differentiated into cardiomyocytes, smooth muscle cells and endothelial cells. Lineage reprogramming of adult somatic cells into iCPCs provides a scalable cell source for drug discovery, disease modeling, and cardiac regenerative therapy.

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“…MESP1 regulates many of the key transcription factors implicated in epithelial-to-mesenchymal transition, such as SNAI1, which downregulates CDH1 (E-cadherin) to allow for cell movement (76). Cardiac progenitors expressing MESP1 and the surface markers KDR, PDGFRA, and CXCR4 (12) transition out of the primitive streak and migrate bilaterally, looping around either side of the embryo in the lateral plate mesoderm to converge at the midline, the site of the future heart. Two distinct progenitor cell populations that arise from the cardiac mesoderm are called first and second heart fields (FHFs and SHFs, respectively), and they provide different regional contributions to the developing heart.…”

Section: Genetic Control Of Cardiac Developmentmentioning

confidence: 99%

Genetic and Epigenetic Regulation of Human Cardiac Reprogramming and Differentiation in Regenerative Medicine

Burridge

Sharma

2015

Annu. Rev. Genet.

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Regeneration or replacement of lost cardiomyocytes within the heart has the potential to revolutionize cardiovascular medicine. Numerous methodologies have been used to achieve this aim, including the engraftment of bone marrow- and heart-derived cells as well as the identification of modulators of adult cardiomyocyte proliferation. Recently, the conversion of human somatic cells into induced pluripotent stem cells and induced cardiomyocyte-like cells has transformed potential approaches toward this goal, and the engraftment of cardiac progenitors derived from human embryonic stem cells into patients is now feasible. Here we review recent advances in our understanding of the genetic and epigenetic control of human cardiogenesis, cardiac differentiation, and the induced reprogramming of somatic cells to cardiomyocytes. We also cover genetic programs for inducing the proliferation of endogenous cardiomyocytes and discuss the genetic state of cells used in cardiac regenerative medicine.

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Defining the earliest step of cardiovascular progenitor specification during embryonic stem cell differentiation

Abstract: Mesp1, the earliest marker of cardiovascular development in vivo, is used to isolate and characterize multipotent cardiovascular progenitors during ESC differentiation.

Cited by 114 publications

References 40 publications

Effect of Human Donor Cell Source on Differentiation and Function of Cardiac Induced Pluripotent Stem Cells

Effect of Human Donor Cell Source on Differentiation and Function of Cardiac Induced Pluripotent Stem Cells

Lineage Reprogramming of Fibroblasts into Proliferative Induced Cardiac Progenitor Cells by Defined Factors

Genetic and Epigenetic Regulation of Human Cardiac Reprogramming and Differentiation in Regenerative Medicine

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