Mai Watanabe1, Hiromu Horie1, Yasutaka Kurata2, Yumiko Inoue1, Tomomi Notsu1, Takayuki Wakimizu1, Maya Adachi1, Kenshiro Yamamoto1, Kumi Morikawa3, Masanari Kuwabara4, Takuki Sakaguchi5, Takayuki Morisaki6, Junichiro Miake7, Motonobu Nishimura8, Motokazu Tsuneto1, Yasuaki Shirayoshi1, Shin Ito9, Masafumi Kitakaze10, Haruaki Ninomiya11, Kazuhiro Yamamoto12, Ichiro Hisatome1. 1. Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science. 2. Department of Physiology II, Kanazawa Medical University. 3. Biomaterials Research Group, Department of Life Science and Biotechnology, Health and Medical Research Institute, National Institute of Advanced Industrial Science and Technology. 4. Intensive Care Unit and Department of Cardiology, Toranomon Hospital. 5. Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine. 6. Division of Molecular Pathology/Department of Internal Medicine IMSUT Hospital, The Institute of Medical Science, The University of Tokyo. 7. Department of Pharmacology, Tottori University Faculty of Medicine. 8. Division of Cardiovascular Surgery, Department of Surgery, Tottori University Faculty of Medicine. 9. Department of Clinical Research and Development, National Cerebral and Cardiovascular Center. 10. Hanwa Daini Senboku Hospital. 11. Department of Biological Regulation, Tottori University Faculty of Medicine. 12. Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine.
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.
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.