Clonally amplified cardiac stem cells are regulated by Sca-1 signaling for efficient cardiovascular regeneration.
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.
Tateishi
Kento
K
Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto 606-8507, Japan.
Ashihara
Eishi
E
Takehara
Naofumi
N
Nomura
Tetsuya
T
Honsho
Shoken
S
Nakagami
Takuo
T
Morikawa
Shigehiro
S
Takahashi
Tomosaburo
T
Ueyama
Tomomi
T
Matsubara
Hiroaki
H
Oh
Hidemasa
H
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
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