title: Intracellular transduction of TAT-Hsp27 fusion protein enhancing cell survival and regeneration capacity of cardiac stem cells in acute myocardial infarction.
abstract: Myocardial infarction (MI) results in the substantial loss of functional cardiomyocytes, which frequently leads to intractable heart disorders. Cardiac stem cells (CSCs) that retain the capacity to replace all cardiac cells might be a promising strategy for providing a source of new functional cardiomyocytes; however, the poor survival and engraftment of transplanted CSCs in the hostile environment of MI critically mitigate their therapeutic benefits. To capitalize their therapeutic potential, an ex vivo strategy in which CSCs were introduced to the recombinant heat shock protein 27 (Hsp27) through a TAT protein transduction domain for increasing the viability and engraftment in the infarcted myocardium was designed. A recombinant TAT fused Hsp27 (TAT-Hsp27) was able to enter CSCs in a dose-dependent manner. CSCs transduced with TAT-Hsp27 expressed not only endogenous Hsp27 but externally introduced Hsp27, resulting in substantial increase of their anti-oxidative and anti-apoptotic properties via suppressing reactive oxygen species production, the MAPKs signaling pathway, and caspase activation. TAT-Hsp27 enabled CSCs to be protected from apoptotic- and hypoxic-induced cell death during in vitro cardiomyogenic differentiation. In vivo studies demonstrated that CSCs transduced TAT-Hsp27 significantly increased the survival and engraftment in the acutely infarcted myocardium, which is closely related to caspase activity suppression. Finally, CSCs transduced TAT-Hsp27 improved cardiac function and attenuated cardiac remodeling in comparison with non-transduced CSCs. Overall, our approach, which is based on the ex vivo intracellular transduction of TAT-Hsp27 into CSCs before myocardial delivery, might be effective in treating MI.
authors.affiliation: Paik Institute for Clinical Research, Inje University College of Medicine, 633-165 Gaegum-dong, Busanjin-gu, Busan 614-735, Republic of Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Paik Institute for Clinical Research, Inje University College of Medicine, 633-165 Gaegum-dong, Busanjin-gu, Busan 614-735, Republic of Korea.
authors.forename: Myoung-Hun
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Paik Institute for Clinical Research, Inje University College of Medicine, 633-165 Gaegum-dong, Busanjin-gu, Busan 614-735, Republic of Korea.
authors.forename: Jong Tae
authors.initials: JT
authors.lastname: Kim
authors.affiliation: Paik Institute for Clinical Research, Inje University College of Medicine, 633-165 Gaegum-dong, Busanjin-gu, Busan 614-735, Republic of Korea.
authors.forename: Won-Jin
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Paik Institute for Clinical Research, Inje University College of Medicine, 633-165 Gaegum-dong, Busanjin-gu, Busan 614-735, Republic of Korea.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Kwang Suk
authors.initials: KS
authors.lastname: Lim
authors.affiliation: Department of Bioengineering, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Jang Kyoung
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Paik Institute for Clinical Research, Inje University College of Medicine, 633-165 Gaegum-dong, Busanjin-gu, Busan 614-735, Republic of Korea. Electronic address: pathyang@inje.ac.kr.
authors.forename: Young Il
authors.initials: YI
authors.lastname: Yang
authors.affiliation: Department of Molecular Science and Technology, Ajou University, San 5, Woncheon, Yeongtong, Suwon 443-749, Republic of Korea.
authors.forename: Ki Dong
authors.initials: KD
authors.lastname: Park
authors.affiliation: Department of Bioengineering, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Kim
mesh_terms: D000208:Acute Disease; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015696:Gene Products, tat / Q000235:genetics*; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006360:Heat-Shock Proteins; D006412:Hematopoietic Stem Cells; D008297:Male; D018832:Molecular Chaperones; D009203:Myocardial Infarction / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration; D014161:Transduction, Genetic; D014760:Viral Fusion Proteins / Q000235:genetics
chemical_list: D000975:Antioxidants; D015696:Gene Products, tat; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; D014760:Viral Fusion Proteins; D020169:Caspases
keywords: Cardiac stem cells; Cell survival; Heat shock protein-27; Myocardial infarction; TAT PTD