Physiological and hypoxic oxygen concentration differentially regulates human c-kit+ cardiac stem cell proliferation and migration

Michael A. Bellio, Claudia D Rodrigues, Ana Marie Landin, Konstantinos E. Hatzistergos, Jeffim Kuznetsov, Victoria Florea, Krystalenia Valasaki, Aisha Khan, Joshua Hare, Ivonne H Schulman

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Cardiac stem cells (CSCs) are being evaluated for their efficacy in the treatment of heart failure. However, numerous factors impair the exogenously delivered cells’ regenerative capabilities. Hypoxia is one stress that contributes to inadequate tissue repair. Here, we tested the hypothesis that hypoxia impairs cell proliferation, survival, and migration of human CSCs relative to physiological and room air oxygen concentrations. Human endomyocardial biopsy-derived CSCs were isolated, selected for c-Kit expression, and expanded in vitro at room air (21% O2). To assess the effect on proliferation, survival, and migration, CSCs were transferred to physiological (5%) or hypoxic (0.5%) O2 concentrations. Physiological O2 levels increased proliferation (P < 0.05) but did not affect survival of CSCs. Although similar growth rates were observed in room air and hypoxia, a significant reduction of ß-galactosidase activity (-4, 203 fluorescent units, P < 0.05), pl6 protein expression (0.58-fold. P < 0.001), and mitochondrial content (0.18-fold. P < 0.001) in hypoxia suggests that transition from high (21%) to low (0.5%) O2 reduces senescence and promotes quiescence. Furthermore, physiological O2 levels increased migration (P < 0.05) compared with room air and hypoxia, and treatment with mesenchymal stem cell-conditioned media rescued CSC migration under hypoxia to levels comparable to physiological O2 migration (2-fold, P < 0.05 relative to CSC media control). Our finding that physiological O2 concentration is optimal for in vitro parameters of CSC biology suggests that standard room air may diminish cell regenerative potential. This study provides novel insights into the modulatory effects of O2 concentration on CSC biology and has important implications for refining stem cell therapies.

Original languageEnglish (US)
Pages (from-to)H1509-H1519
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume311
Issue number6
DOIs
StatePublished - Dec 1 2016

Fingerprint

Cell Movement
Stem Cells
Cell Proliferation
Oxygen
Air
Cell Biology
Galactosidases
Survival
Conditioned Culture Medium
Cell- and Tissue-Based Therapy
Treatment Failure
Mesenchymal Stromal Cells
Hypoxia
Cell Survival
Heart Failure
Biopsy
Growth

Keywords

  • Cardiovascular disease
  • Cardiovascular progenitor/stem cells
  • Cell transplantation
  • Regenerative medicine

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Physiological and hypoxic oxygen concentration differentially regulates human c-kit+ cardiac stem cell proliferation and migration. / Bellio, Michael A.; Rodrigues, Claudia D; Landin, Ana Marie; Hatzistergos, Konstantinos E.; Kuznetsov, Jeffim; Florea, Victoria; Valasaki, Krystalenia; Khan, Aisha; Hare, Joshua; Schulman, Ivonne H.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 311, No. 6, 01.12.2016, p. H1509-H1519.

Research output: Contribution to journalArticle

Bellio, Michael A. ; Rodrigues, Claudia D ; Landin, Ana Marie ; Hatzistergos, Konstantinos E. ; Kuznetsov, Jeffim ; Florea, Victoria ; Valasaki, Krystalenia ; Khan, Aisha ; Hare, Joshua ; Schulman, Ivonne H. / Physiological and hypoxic oxygen concentration differentially regulates human c-kit+ cardiac stem cell proliferation and migration. In: American Journal of Physiology - Heart and Circulatory Physiology. 2016 ; Vol. 311, No. 6. pp. H1509-H1519.
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AU - Kuznetsov, Jeffim

AU - Florea, Victoria

AU - Valasaki, Krystalenia

AU - Khan, Aisha

AU - Hare, Joshua

AU - Schulman, Ivonne H

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AB - Cardiac stem cells (CSCs) are being evaluated for their efficacy in the treatment of heart failure. However, numerous factors impair the exogenously delivered cells’ regenerative capabilities. Hypoxia is one stress that contributes to inadequate tissue repair. Here, we tested the hypothesis that hypoxia impairs cell proliferation, survival, and migration of human CSCs relative to physiological and room air oxygen concentrations. Human endomyocardial biopsy-derived CSCs were isolated, selected for c-Kit expression, and expanded in vitro at room air (21% O2). To assess the effect on proliferation, survival, and migration, CSCs were transferred to physiological (5%) or hypoxic (0.5%) O2 concentrations. Physiological O2 levels increased proliferation (P < 0.05) but did not affect survival of CSCs. Although similar growth rates were observed in room air and hypoxia, a significant reduction of ß-galactosidase activity (-4, 203 fluorescent units, P < 0.05), pl6 protein expression (0.58-fold. P < 0.001), and mitochondrial content (0.18-fold. P < 0.001) in hypoxia suggests that transition from high (21%) to low (0.5%) O2 reduces senescence and promotes quiescence. Furthermore, physiological O2 levels increased migration (P < 0.05) compared with room air and hypoxia, and treatment with mesenchymal stem cell-conditioned media rescued CSC migration under hypoxia to levels comparable to physiological O2 migration (2-fold, P < 0.05 relative to CSC media control). Our finding that physiological O2 concentration is optimal for in vitro parameters of CSC biology suggests that standard room air may diminish cell regenerative potential. This study provides novel insights into the modulatory effects of O2 concentration on CSC biology and has important implications for refining stem cell therapies.

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