Document Detail

Insulin-like growth factor-1 receptor identifies a pool of human cardiac stem cells with superior therapeutic potential for myocardial regeneration.
MedLine Citation:
PMID:  21546606     Owner:  NLM     Status:  MEDLINE    
RATIONALE: Age and coronary artery disease may negatively affect the function of human cardiac stem cells (hCSCs) and their potential therapeutic efficacy for autologous cell transplantation in the failing heart.
OBJECTIVE: Insulin-like growth factor (IGF)-1, IGF-2, and angiotensin II (Ang II), as well as their receptors, IGF-1R, IGF-2R, and AT1R, were characterized in c-kit(+) hCSCs to establish whether these systems would allow us to separate hCSC classes with different growth reserve in the aging and diseased myocardium.
METHODS AND RESULTS: C-kit(+) hCSCs were collected from myocardial samples obtained from 24 patients, 48 to 86 years of age, undergoing elective cardiac surgery for coronary artery disease. The expression of IGF-1R in hCSCs recognized a young cell phenotype defined by long telomeres, high telomerase activity, enhanced cell proliferation, and attenuated apoptosis. In addition to IGF-1, IGF-1R(+) hCSCs secreted IGF-2 that promoted myocyte differentiation. Conversely, the presence of IGF-2R and AT1R, in the absence of IGF-1R, identified senescent hCSCs with impaired growth reserve and increased susceptibility to apoptosis. The ability of IGF-1R(+) hCSCs to regenerate infarcted myocardium was then compared with that of unselected c-kit(+) hCSCs. IGF-1R(+) hCSCs improved cardiomyogenesis and vasculogenesis. Pretreatment of IGF-1R(+) hCSCs with IGF-2 resulted in the formation of more mature myocytes and superior recovery of ventricular structure.
CONCLUSIONS: hCSCs expressing only IGF-1R synthesize both IGF-1 and IGF-2, which are potent modulators of stem cell replication, commitment to the myocyte lineage, and myocyte differentiation, which points to this hCSC subset as the ideal candidate cell for the management of human heart failure.
Domenico D'Amario; Mauricio C Cabral-Da-Silva; Hanqiao Zheng; Claudia Fiorini; Polina Goichberg; Elisabeth Steadman; João Ferreira-Martins; Fumihiro Sanada; Marco Piccoli; Donato Cappetta; David A D'Alessandro; Robert E Michler; Toru Hosoda; Luigi Anastasia; Marcello Rota; Annarosa Leri; Piero Anversa; Jan Kajstura
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-05-05
Journal Detail:
Title:  Circulation research     Volume:  108     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-10     Completed Date:  2011-08-12     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1467-81     Citation Subset:  IM    
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MeSH Terms
Angiotensin II / metabolism
Cell Differentiation
Coronary Artery Disease / metabolism*,  pathology,  therapy
Insulin-Like Growth Factor I / biosynthesis
Insulin-Like Growth Factor II / metabolism
Myocardial Infarction / metabolism*,  pathology,  therapy
Myocardium / metabolism*,  pathology
Myocytes, Cardiac / metabolism*,  pathology
Receptor, IGF Type 1 / metabolism*
Receptor, IGF Type 2 / metabolism
Stem Cell Transplantation
Stem Cells / metabolism*,  pathology
Transplantation, Autologous
Grant Support
P01 AG023071/AG/NIA NIH HHS; P01 AG023071-05/AG/NIA NIH HHS; P01 HL092868/HL/NHLBI NIH HHS; P01 HL092868-03/HL/NHLBI NIH HHS; R01 AG015756/AG/NIA NIH HHS; R01 AG015756-13/AG/NIA NIH HHS; R01 AG017042/AG/NIA NIH HHS; R01 AG017042-05/AG/NIA NIH HHS; R01 AG017042-10/AG/NIA NIH HHS; R01 AG026107/AG/NIA NIH HHS; R01 AG026107-05/AG/NIA NIH HHS; R01 AG037490/AG/NIA NIH HHS; R01 AG037490-03/AG/NIA NIH HHS; R01 AG037495/AG/NIA NIH HHS; R01 AG037495-01A1/AG/NIA NIH HHS; R01 HL039902/HL/NHLBI NIH HHS; R01 HL039902-20/HL/NHLBI NIH HHS; R01 HL065573/HL/NHLBI NIH HHS; R01 HL065573-08/HL/NHLBI NIH HHS; R01 HL065577/HL/NHLBI NIH HHS; R01 HL065577-05/HL/NHLBI NIH HHS; R01 HL075480/HL/NHLBI NIH HHS; R01 HL075480-05/HL/NHLBI NIH HHS; R01 HL091021/HL/NHLBI NIH HHS; R01 HL091021-04/HL/NHLBI NIH HHS; R01 HL105532/HL/NHLBI NIH HHS; R01 HL105532-02/HL/NHLBI NIH HHS; R01 HL111183/HL/NHLBI NIH HHS; R01 HL114346/HL/NHLBI NIH HHS; R01 HL114346-01/HL/NHLBI NIH HHS; R37 HL081737/HL/NHLBI NIH HHS; R37 HL081737-07/HL/NHLBI NIH HHS
Reg. No./Substance:
0/IGF2 protein, human; 0/Receptor, IGF Type 2; 11128-99-7/Angiotensin II; 67763-96-6/Insulin-Like Growth Factor I; 67763-97-7/Insulin-Like Growth Factor II; EC, IGF Type 1

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