Myocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells

Abstract Cardiomyocyte regeneration is limited in adults. The adipose tissue-derived stromal vascular fraction (Ad-SVF) contains pluripotent stem cells that rarely transdifferentiate into spontaneously beating cardiomyocyte-like cells (beating CMs). However, the characteristics of beating CMs and th...

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Autores principales: Shinichiro Takashima, Soichiro Usui, Oto Inoue, Chiaki Goten, Kosei Yamaguchi, Yusuke Takeda, Shihe Cui, Yoshio Sakai, Kenshi Hayashi, Kenji Sakata, Masa-aki Kawashiri, Masayuki Takamura
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Publicado: Nature Portfolio 2021
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spelling oai:doaj.org-article:3ac118e615d34fb6a9dbaa318df783632021-12-02T14:01:19ZMyocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells10.1038/s41598-020-80848-32045-2322https://doaj.org/article/3ac118e615d34fb6a9dbaa318df783632021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80848-3https://doaj.org/toc/2045-2322Abstract Cardiomyocyte regeneration is limited in adults. The adipose tissue-derived stromal vascular fraction (Ad-SVF) contains pluripotent stem cells that rarely transdifferentiate into spontaneously beating cardiomyocyte-like cells (beating CMs). However, the characteristics of beating CMs and the factors that regulate the differentiation of Ad-SVF toward the cardiac lineage are unknown. We developed a simple culture protocol under which the adult murine inguinal Ad-SVF reproducibly transdifferentiates into beating CMs without induction. The beating CMs showed the striated ventricular phenotype of cardiomyocytes and synchronised oscillation of the intracellular calcium concentration among cells on day 28 of Ad-SVF primary culture. We also identified beating CM-fated progenitors (CFPs) and performed single-cell transcriptome analysis of these CFPs. Among 491 transcription factors that were differentially expressed (≥ 1.75-fold) in CFPs and the beating CMs, myocyte-specific enhancer 2c (Mef2c) was key. Transduction of Ad-SVF cells with Mef2c using a lentiviral vector yielded CFPs and beating CMs with ~ tenfold higher cardiac troponin T expression, which was abolished by silencing of Mef2c. Thus, we identified the master gene required for transdifferentiation of Ad-SVF into beating CMs. These findings will facilitate the development of novel cardiac regeneration therapies based on gene-modified, cardiac lineage-directed Ad-SVF cells.Shinichiro TakashimaSoichiro UsuiOto InoueChiaki GotenKosei YamaguchiYusuke TakedaShihe CuiYoshio SakaiKenshi HayashiKenji SakataMasa-aki KawashiriMasayuki TakamuraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Shinichiro Takashima
Soichiro Usui
Oto Inoue
Chiaki Goten
Kosei Yamaguchi
Yusuke Takeda
Shihe Cui
Yoshio Sakai
Kenshi Hayashi
Kenji Sakata
Masa-aki Kawashiri
Masayuki Takamura
Myocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells
description Abstract Cardiomyocyte regeneration is limited in adults. The adipose tissue-derived stromal vascular fraction (Ad-SVF) contains pluripotent stem cells that rarely transdifferentiate into spontaneously beating cardiomyocyte-like cells (beating CMs). However, the characteristics of beating CMs and the factors that regulate the differentiation of Ad-SVF toward the cardiac lineage are unknown. We developed a simple culture protocol under which the adult murine inguinal Ad-SVF reproducibly transdifferentiates into beating CMs without induction. The beating CMs showed the striated ventricular phenotype of cardiomyocytes and synchronised oscillation of the intracellular calcium concentration among cells on day 28 of Ad-SVF primary culture. We also identified beating CM-fated progenitors (CFPs) and performed single-cell transcriptome analysis of these CFPs. Among 491 transcription factors that were differentially expressed (≥ 1.75-fold) in CFPs and the beating CMs, myocyte-specific enhancer 2c (Mef2c) was key. Transduction of Ad-SVF cells with Mef2c using a lentiviral vector yielded CFPs and beating CMs with ~ tenfold higher cardiac troponin T expression, which was abolished by silencing of Mef2c. Thus, we identified the master gene required for transdifferentiation of Ad-SVF into beating CMs. These findings will facilitate the development of novel cardiac regeneration therapies based on gene-modified, cardiac lineage-directed Ad-SVF cells.
format article
author Shinichiro Takashima
Soichiro Usui
Oto Inoue
Chiaki Goten
Kosei Yamaguchi
Yusuke Takeda
Shihe Cui
Yoshio Sakai
Kenshi Hayashi
Kenji Sakata
Masa-aki Kawashiri
Masayuki Takamura
author_facet Shinichiro Takashima
Soichiro Usui
Oto Inoue
Chiaki Goten
Kosei Yamaguchi
Yusuke Takeda
Shihe Cui
Yoshio Sakai
Kenshi Hayashi
Kenji Sakata
Masa-aki Kawashiri
Masayuki Takamura
author_sort Shinichiro Takashima
title Myocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells
title_short Myocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells
title_full Myocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells
title_fullStr Myocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells
title_full_unstemmed Myocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells
title_sort myocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/3ac118e615d34fb6a9dbaa318df78363
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