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Stem Cells. 2019 Jan 10. doi: 10.1002/stem.2970. [Epub ahead of print]

Hypoxia Prevents Mitochondrial Dysfunction and Senescence in Human c-Kit+ Cardiac Progenitor Cells.

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Department of Biology and Integrated Regenerative Research Institute, San Diego State University, San Diego, California.
Division of Cardiology, Sharp Hospital, San Diego, California.
The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, University of California San Diego, La Jolla.


Senescence-associated dysfunction deleteriously affects biological activites of human c-Kit+ cardiac progenitor cells (hCPCs), particularly under conditions of in vitro culture. In comparison, preservation of self-renewal and decreases in mitochondrial reactive oxygen species (ROS) are characteristic of murine CPCs in vivo that reside within hypoxic niches. Recapitulating hypoxic niche oxygen tension conditions of ~1% O2 in vitro for expansion of hCPCs rather than typical normoxic cell culture conditions (21% O2 ) could provide significant improvement of functional and biological activity of hCPCs. hCPCs were isolated and expanded under permanent hypoxia (hCPC-1%) or normoxia (hCPC-21%) from left ventricular tissue explants collected during left ventricular assist device implantation. hCPC-1% exhibit increased self-renewal and suppression of senescence characteristics relative to hCPC-21%. Oxidative stress contributed to higher susceptibility to apoptosis, as well as decreased mitochondrial function in hCPC-21%. Hypoxia prevented accumulation of dysfunctional mitochondria, supporting higher oxygen consumption rates and mitochondrial membrane potential. Mitochondrial ROS was an upstream mediator of senescence since treatment of hCPC-1% with mitochondrial inhibitor antimycin A recapitulated mitochondrial dysfunction and senescence observed in hCPC-21%. NAD+ /NADH ratio and autophagic flux, key factors for mitochondrial function, were higher in hCPC-1%, but hCPC-21% were highly dependent on BNIP3/NIX-mediated mitophagy to maintain mitochondrial function. Collectively, results demonstrate that supraphysiological oxygen tension during in vitro expansion initiates a downward spiral of oxidative stress, mitochondrial dysfunction, and cellular energy imbalance culminating in early proliferation arrest of hCPCs. Senescence is inhibited by preventing ROS through hypoxic culture of hCPCs. SIGNIFICANCE STATEMENT: hCPC biological function is hampered by limited expansion potential and early replicative senescence. Permanent hypoxia (1% O2 ) preserved clonogenicity and mitochondrial function of hCPC derived from heart failure (HF) patients while maintaining high levels of intracellular NAD+ /NADH ratio and suppressing ROS and oxidative stress.


ROS; autophagy; heart; human; mitochondria; stem cells


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