Physiological and hypoxic oxygen concentration differentially regulates human c-Kit+ cardiac stem cell proliferation and migration.
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%) O2concentrations. Physiological O2levels 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 β-galactosidase activity (-4,203 fluorescent units, P < 0.05), p16 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%) O2reduces senescence and promotes quiescence. Furthermore, physiological O2levels 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 O2migration (2-fold, P < 0.05 relative to CSC media control). Our finding that physiological O2concentration 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 O2concentration on CSC biology and has important implications for refining stem cell therapies.
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and.
Michael A
MA
Bellio
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and.
Claudia O
CO
Rodrigues
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and.
Ana Marie
AM
Landin
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and.
Konstantinos E
KE
Hatzistergos
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and.
Jeffim
J
Kuznetsov
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and.
Victoria
V
Florea
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and.
Krystalenia
K
Valasaki
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and.
Aisha
A
Khan
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and.
Joshua M
JM
Hare
Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and ischulman@med.miami.edu.|Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, Florida.
Ivonne Hernandez
IH
Schulman
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism; D009206:Myocardium / Q000166:cytology; D010100:Oxygen / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism* / Q000502:physiology; D001616:beta-Galactosidase / Q000378:metabolism
C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D019009:Proto-Oncogene Proteins c-kit; D001616:beta-Galactosidase; D010100:Oxygen
cardiovascular disease; cardiovascular progenitor/stem cells; cell transplantation; regenerative medicine
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