Direct reprogramming of adult adipose-derived regenerative cells toward cardiomyocytes using six transcriptional factors
Shingo Narita,
Kazumasa Unno,
Katsuhiro Kato,
Yusuke Okuno,
Yoshitaka Sato,
Yusuke Tsumura,
Yusuke Fujikawa,
Yuuki Shimizu,
Ryo Hayashida,
Kazuhisa Kondo,
Rei Shibata,
Toyoaki Murohara
Affiliations
Shingo Narita
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Kazumasa Unno
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Corresponding author
Katsuhiro Kato
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Yusuke Okuno
Department of Virology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
Yoshitaka Sato
Department of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; PRESTO, Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan
Yusuke Tsumura
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Yusuke Fujikawa
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Yuuki Shimizu
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Ryo Hayashida
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Kazuhisa Kondo
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Rei Shibata
Department of Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Toyoaki Murohara
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Summary: It is widely accepted that adipose-derived regenerative cells (ADRCs) can differentiate into mesodermal lineage cells. However, reprogramming adult ADRCs into mature cardiomyocytes is challenging. We investigated the induction of myocardial differentiation in ADRCs via direct reprogramming using lentiviral gene transfer. First, we identified candidate transcriptional factors by performing RNA sequencing and ultimately confirmed that the combination of six unique factors (Baf60c, Gata4, Gata6, Klf15, Mef2a, and Myocd) could efficiently express enhanced green fluorescent protein (GFP) in ADRCs isolated from adult alpha-myosin heavy chain promoter-driven GFP transgenic mice. The GFP-positive ADRCs induced by six factors (6F-ADRCs) expressed multiple cardiac genes and revealed cardiac differentiation in bioinformatic analysis. Moreover, injection of 6F-ADRCs into acute myocardial infarcted tissues in vivo resulted in the improvement of survival rate, fractional shortening, and reduction of infarction scar area. This study provides an alternative method for direct reprogramming of adult ADRCs into cardiomyocytes.
