Esm1 and Stc1 as Angiogenic Factors Responsible for Protective Actions of Adipose-Derived Stem Cell Sheets on Chronic Heart Failure After Rat Myocardial Infarction

Mai Watanabe; Hiromu Horie; Yasutaka Kurata; Yumiko Inoue; Tomomi Notsu; Takayuki Wakimizu; Maya Adachi; Kenshiro Yamamoto; Kumi Morikawa; Masanari Kuwabara; Takuki Sakaguchi; Takayuki Morisaki; Junichiro Miake; Motonobu Nishimura; Motokazu Tsuneto; Yasuaki Shirayoshi; Shin Ito; Masafumi Kitakaze; Haruaki Ninomiya; Kazuhiro Yamamoto; Ichiro Hisatome

doi:10.1253/circj.CJ-20-0877

Basic Science

Esm1 and Stc1 as Angiogenic Factors Responsible for Protective Actions of Adipose-Derived Stem Cell Sheets on Chronic Heart Failure After Rat Myocardial Infarction

Mai Watanabe, Hiromu Horie, Yasutaka Kurata, Yumiko Inoue, Tomomi Notsu, Takayuki Wakimizu, Maya Adachi, Kenshiro Yamamoto, Kumi Morikawa, Masanari Kuwabara, Takuki Sakaguchi, Takayuki Morisaki, Junichiro Miake, Motonobu Nishimura, Motokazu Tsuneto, Yasuaki Shirayoshi, Shin Ito, Masafumi Kitakaze, Haruaki Ninomiya, Kazuhiro Yamamoto, Ichiro Hisatome

Author information

Mai Watanabe
Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science [Japan]
Hiromu Horie
Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science [Japan]
Yasutaka Kurata
Department of Physiology II, Kanazawa Medical University [Japan]
Yumiko Inoue
Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science [Japan]
Tomomi Notsu
Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science [Japan]
Takayuki Wakimizu
Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science [Japan]
Maya Adachi
Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science [Japan]
Kenshiro Yamamoto
Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science [Japan]
Kumi Morikawa
Biomaterials Research Group, Department of Life Science and Biotechnology, Health and Medical Research Institute, National Institute of Advanced Industrial Science and Technology [Japan]
Masanari Kuwabara
Intensive Care Unit and Department of Cardiology, Toranomon Hospital [Japan]
Takuki Sakaguchi
Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine [Japan]
Takayuki Morisaki
Division of Molecular Pathology/Department of Internal Medicine IMSUT Hospital, The Institute of Medical Science, The University of Tokyo [Japan]
Junichiro Miake
Department of Pharmacology, Tottori University Faculty of Medicine [Japan]
Motonobu Nishimura
Division of Cardiovascular Surgery, Department of Surgery, Tottori University Faculty of Medicine [Japan]
Motokazu Tsuneto
Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science [Japan]
Yasuaki Shirayoshi
Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science [Japan]
Shin Ito
Department of Clinical Research and Development, National Cerebral and Cardiovascular Center [Japan]
Masafumi Kitakaze
Hanwa Daini Senboku Hospital [Japan]
Haruaki Ninomiya
Department of Biological Regulation, Tottori University Faculty of Medicine [Japan]
Kazuhiro Yamamoto
Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine [Japan]
Ichiro Hisatome
Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science [Japan]

Keywords: Adipose-derived stem cell, Cell sheet, Esm1, RNA sequencing, Stc1

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Supplementary material

2021 Volume 85 Issue 5 Pages 657-666

DOI https://doi.org/10.1253/circj.CJ-20-0877

Editorial (85-5 pp. 667-668)

Browse “Advance online publication” version

Details

Abstract

Background:Although adipose-derived stem cell (ADSC) sheets improve the cardiac function after myocardial infarction (MI), underlying mechanisms remain to be elucidated. The aim of this study was to determine the fate of transplanted ADSC sheets and candidate angiogenic factors released from ADSCs for their cardiac protective actions.

Methods and Results:MI was induced by ligation of the left anterior descending coronary artery. Sheets of transgenic (Tg)-ADSCs expressing green fluorescence protein (GFP) and luciferase or wild-type (WT)-ADSCs were transplanted 1 week after MI. Both WT- and Tg-ADSC sheets improved cardiac functions evaluated by echocardiography at 3 and 5 weeks after MI. Histological examination at 5 weeks after MI demonstrated that either sheet suppressed fibrosis and increased vasculogenesis. Luciferase signals from Tg-ADSC sheets were detected at 1 and 2 weeks, but not at 4 weeks, after transplantation. RNA sequencing of PKH (yellow-orange fluorescent dye with long aliphatic tails)-labeled Tg-ADSCs identified mRNAs of 4 molecules related to angiogenesis, including those of Esm1 and Stc1 that increased under hypoxia. Administration of Esm1 or Stc1 promoted tube formation by human umbilical vein endothelial cells.

Conclusions:ADSC sheets improved cardiac contractile functions after MI by suppressing cardiac fibrosis and enhancing neovascularization. Transplanted ADSCs existed for >2 weeks on MI hearts and produced the angiogenic factors Esm1 and Stc1, which may improve cardiac functions after MI.

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