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 Yamagishi & 2 others Keiichi Fukuda, Masaki Ieda

Research output: Contribution to journalArticle

23 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

Fingerprint

Sendai virus
Myocardial Infarction
Fibroblasts
Retroviridae
Cardiac Myocytes
Fibrosis
Regenerative Medicine
Insertional Mutagenesis
Transgenes
Regeneration
Gene Expression
Genes

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Direct In Vivo Reprogramming with Sendai Virus Vectors Improves Cardiac Function after Myocardial Infarction. / Miyamoto, Kazutaka; Akiyama, Mizuha; Tamura, Fumiya; Isomi, Mari; Yamakawa, Hiroyuki; Sadahiro, Taketaro; Muraoka, Naoto; Kojima, Hidenori; Haginiwa, Sho; Kurotsu, Shota; Tani, Hidenori; Wang, Li; Qian, Li; Inoue, Makoto; Ide, Yoshinori; Kurokawa, Junko; Yamamoto, Tsunehisa; Seki, Tomohisa; Aeba, Ryo; Yamagishi, Hiroyuki; Fukuda, Keiichi; Ieda, Masaki.

In: Cell Stem Cell, 01.01.2017.

Research output: Contribution to journalArticle

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, Yamagishi, H, Fukuda, K & Ieda, M 2017, '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
Miyamoto, Kazutaka ; Akiyama, Mizuha ; Tamura, Fumiya ; Isomi, Mari ; Yamakawa, Hiroyuki ; Sadahiro, Taketaro ; Muraoka, Naoto ; Kojima, Hidenori ; Haginiwa, Sho ; Kurotsu, Shota ; Tani, Hidenori ; Wang, Li ; Qian, Li ; Inoue, Makoto ; Ide, Yoshinori ; Kurokawa, Junko ; Yamamoto, Tsunehisa ; Seki, Tomohisa ; Aeba, Ryo ; Yamagishi, Hiroyuki ; Fukuda, Keiichi ; Ieda, Masaki. / Direct In Vivo Reprogramming with Sendai Virus Vectors Improves Cardiac Function after Myocardial Infarction. In: Cell Stem Cell. 2017.
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AU - Yamakawa, Hiroyuki

AU - Sadahiro, Taketaro

AU - Muraoka, Naoto

AU - Kojima, Hidenori

AU - Haginiwa, Sho

AU - Kurotsu, Shota

AU - Tani, Hidenori

AU - Wang, Li

AU - Qian, Li

AU - Inoue, Makoto

AU - Ide, Yoshinori

AU - Kurokawa, Junko

AU - Yamamoto, Tsunehisa

AU - Seki, Tomohisa

AU - Aeba, Ryo

AU - Yamagishi, Hiroyuki

AU - Fukuda, Keiichi

AU - Ieda, Masaki

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N2 - 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.

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