title: Insulin-like growth factor-1 receptor identifies a pool of human cardiac stem cells with superior therapeutic potential for myocardial regeneration.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: D'Amario
authors.forename: Mauricio C
authors.initials: MC
authors.lastname: Cabral-Da-Silva
authors.forename: Hanqiao
authors.initials: H
authors.lastname: Zheng
authors.forename: Claudia
authors.initials: C
authors.lastname: Fiorini
authors.forename: Polina
authors.initials: P
authors.lastname: Goichberg
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Steadman
authors.forename: João
authors.initials: J
authors.lastname: Ferreira-Martins
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sanada
authors.forename: Marco
authors.initials: M
authors.lastname: Piccoli
authors.forename: Donato
authors.initials: D
authors.lastname: Cappetta
authors.forename: David A
authors.initials: DA
authors.lastname: D'Alessandro
authors.forename: Robert E
authors.initials: RE
authors.lastname: Michler
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoda
authors.forename: Luigi
authors.initials: L
authors.lastname: Anastasia
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D002454:Cell Differentiation; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D012038:Regeneration; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D014182:Transplantation, Autologous
chemical_list: C035170:IGF2 protein, human; D017527:Receptor, IGF Type 2; D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1