title: Generation of Induced Cardiospheres via Reprogramming of Skin Fibroblasts for Myocardial Regeneration.
abstract: Recent pre-clinical and clinical studies have suggested that endogenous cardiospheres (eCS) are potentially safe and effective for cardiac regeneration following myocardial infarction (MI). Nevertheless the preparation of autologous eCS requires invasive myocardial biopsy with limited yield. We describe a novel approach to generate induced cardiospheres (iCS) from adult skin fibroblasts via somatic reprogramming. After infection with Sox2, Klf4, and Oct4, iCS were generated from mouse adult skin fibroblasts treated with Gsk3β inhibitor-(2'Z,3'E)- 6-Bromoindirubin-3'-oxime and Oncostatin M. They resembled eCS, but contained a higher percentage of cells expressing Mesp1, Isl1, and Nkx2.5. They were differentiated into functional cardiomyocytes in vitro with similar electrophysiological properties, calcium transient and contractile function to eCS and mouse embryonic stem cell-derived cardiomyocytes. Transplantation of iCS (1 × 106cells) into mouse myocardium following MI had similar effects to transplantation of eCS but significantly better than saline or fibroblast in improving left ventricular ejection fraction, increasing anterior/septal ventricular wall thickness and capillary density in the infarcted region 4 weeks after transplantation. No tumor formation was observed. iCS generated from adult skin fibroblasts by somatic reprogramming and a cocktail of Gsk3β inhibitor-6-Bromoindirubin-3'-oxime and Oncostatin M may represent a novel source for cell therapy in MI. Stem Cells 2016;34:2693-2706.
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China.|Shenzhen Institutes of Research and Innovation, the University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Jian-Yong
authors.initials: JY
authors.lastname: Xu
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Yee-Ki
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Xinru
authors.initials: X
authors.lastname: Ran
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Song-Yan
authors.initials: SY
authors.lastname: Liao
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China.|Shenzhen Institutes of Research and Innovation, the University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Ka-Wing
authors.initials: KW
authors.lastname: Au
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Wing-Hon
authors.initials: WH
authors.lastname: Lai
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China.|Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, China.|Laboratory of Chromatin and Human Disease, Key Laboratory of Regenerative Biology of the Chinese Academy of Sciences and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Esteban
authors.affiliation: Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, SAR, China.|Shenzhen Institutes of Research and Innovation, the University of Hong Kong, Hong Kong, SAR, China.|Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, China.|Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D053683:Oncostatin M / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D061251:Primary Cell Culture; D012038:Regeneration / Q000502:physiology*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018874:Spheroids, Cellular / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D014161:Transduction, Genetic; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: C483321:6-bromoindirubin-3'-oxime; D007211:Indoles; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; D010091:Oximes; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D053683:Oncostatin M; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D002118:Calcium
keywords: Cardiac progenitor cells; Cardiospheres; Myocardial regeneration; Skin fibroblast; Somatic reprogramming