Insulin-like growth factor-1 receptor identifies a pool of human cardiac stem cells with superior therapeutic potential for myocardial regeneration

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

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1467-1481
Number of pages15
JournalCirculation research
Volume108
Issue number12
DOIs
StatePublished - Jun 10 2011

Keywords

  • angiotensin II
  • cell death
  • cell proliferation
  • cell senescence
  • insulin-like growth factor I
  • insulin-like growth factor II

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    D'Amario, D., Cabral-Da-Silva, M. C., Zheng, H., Fiorini, C., Goichberg, P., Steadman, E., Ferreira-Martins, J., Sanada, F., Piccoli, M., Cappetta, D., D'Alessandro, D. A., Michler, R. E., Hosoda, T., Anastasia, L., Rota, M., Leri, A., Anversa, P., & Kajstura, J. (2011). Insulin-like growth factor-1 receptor identifies a pool of human cardiac stem cells with superior therapeutic potential for myocardial regeneration. Circulation research, 108(12), 1467-1481. https://doi.org/10.1161/CIRCRESAHA.111.240648