Direct In Vivo Reprogramming with Sendai Virus Vectors Improves Cardiac Function after Myocardial Infarction

Kazutaka Miyamoto, Mizuha Akiyama, Fumiya Tamura, Mari Isomi, Hiroyuki Yamakawa, Taketaro Sadahiro, Naoto Muraoka, Hidenori Kojima, Sho Haginiwa, Shota Kurotsu, Hidenori Tani, Li Wang, Li Qian, Makoto Inoue, Yoshinori Ide, Junko Kurokawa, Tsunehisa Yamamoto, Tomohisa Seki, Ryo Aeba, Hiroyuki YamagishiKeiichi Fukuda, Masaki Ieda

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31 Citations (Scopus)

Abstract

Direct cardiac reprogramming holds great promise for regenerative medicine. We previously generated directly reprogrammed induced cardiomyocyte-like cells (iCMs) by overexpression of Gata4, Mef2c, and Tbx5 (GMT) using retrovirus vectors. However, integrating vectors pose risks associated with insertional mutagenesis and disruption of gene expression and are inefficient. Here, we show that Sendai virus (SeV) vectors expressing cardiac reprogramming factors efficiently and rapidly reprogram both mouse and human fibroblasts into integration-free iCMs via robust transgene expression. SeV-GMT generated 100-fold more beating iCMs than retroviral-GMT and shortened the duration to induce beating cells from 30 to 10 days in mouse fibroblasts. In vivo lineage tracing revealed that the gene transfer of SeV-GMT was more efficient than retroviral-GMT in reprogramming resident cardiac fibroblasts into iCMs in mouse infarct hearts. Moreover, SeV-GMT improved cardiac function and reduced fibrosis after myocardial infarction. Thus, efficient, non-integrating SeV vectors may serve as a powerful system for cardiac regeneration. Ieda and colleagues show that non-integrating Sendai virus (SeV) vectors expressing cardiac reprogramming factors efficiently reprogrammed mouse and human fibroblasts into induced cardiomyocyte-like cells. In vivo delivery of SeV vectors enhanced in vivo cardiac reprogramming compared to conventional retrovirus vectors, improved cardiac function, and reduced fibrosis after myocardial infarction.

Original languageEnglish
JournalCell Stem Cell
DOIs
Publication statusAccepted/In press - 2017 Jan 1

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Keywords

  • Cardiomyocyte
  • Fibroblast
  • Integration
  • Myocardial infarction
  • Regeneration
  • Reprogramming
  • Sendai virus

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Miyamoto, K., Akiyama, M., Tamura, F., Isomi, M., Yamakawa, H., Sadahiro, T., Muraoka, N., Kojima, H., Haginiwa, S., Kurotsu, S., Tani, H., Wang, L., Qian, L., Inoue, M., Ide, Y., Kurokawa, J., Yamamoto, T., Seki, T., Aeba, R., ... Ieda, M. (Accepted/In press). Direct In Vivo Reprogramming with Sendai Virus Vectors Improves Cardiac Function after Myocardial Infarction. Cell Stem Cell. https://doi.org/10.1016/j.stem.2017.11.010