title: Clonally amplified cardiac stem cells are regulated by Sca-1 signaling for efficient cardiovascular regeneration.
abstract: Recent studies have shown that cardiac stem cells (CSCs) from the adult mammalian heart can give rise to functional cardiomyocytes; however, the definite surface markers to identify a definitive single entity of CSCs and the molecular mechanisms regulating their growth are so far unknown. Here, we demonstrate a single-cell deposition analysis to isolate individually selected CSCs from adult murine hearts and investigate the signals required for their proliferation and survival. Clonally proliferated CSCs express stem cell antigen-1 (Sca-1) with embryonic stem (ES) cell-like and mesenchymal cell-like characteristics and are associated with telomerase reverse transcriptase (TERT). Using a transgene that expresses a GFP reporter under the control of the TERT promoter, we demonstrated that TERT(GFP)-positive fractions from the heart were enriched for cells expressing Sca-1. Knockdown of Sca-1 transcripts in CSCs led to retarded ex vivo expansion and apoptosis through Akt inactivation. We also show that ongoing CSC proliferation and survival after direct cell-grafting into ischemic myocardium require Sca-1 to upregulate the secreted paracrine effectors that augment neoangiogenesis and limit cardiac apoptosis. Thus, Sca-1 might be an essential component to promote CSC proliferation and survival to directly facilitate early engraftment, and might indirectly exert the effects on late cardiovascular differentiation after CSC transplantation.
authors.affiliation: Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto 606-8507, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Tateishi
authors.forename: Eishi
authors.initials: E
authors.lastname: Ashihara
authors.forename: Naofumi
authors.initials: N
authors.lastname: Takehara
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nomura
authors.forename: Shoken
authors.initials: S
authors.lastname: Honsho
authors.forename: Takuo
authors.initials: T
authors.lastname: Nakagami
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Morikawa
authors.forename: Tomosaburo
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ueyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Oh
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002999:Clone Cells / Q000166:cytology / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D006085:Graft Survival / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D019899:Paracrine Communication / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012038:Regeneration / Q000502:physiology*; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D049452:Green Fluorescent Proteins; D051057:Proto-Oncogene Proteins c-akt; D019098:Telomerase; C509187:Tert protein, mouse