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

ABSTRACT: Senescence-associated dysfunction deleteriously affects biological activities 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 characteristics 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 activities of hCPCs. hCPCs were isolated and expanded under permanent hypoxic (hCPC-1%) or normoxic (hCPC-21%) conditions 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, which are 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. Overall, 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. Stem Cells 2019;37:555-567.

SUBMITTER: Korski KI

PROVIDER: S-EPMC6588544 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Korski Kelli I KI Kubli Dieter A DA Wang Bingyan J BJ Khalafalla Farid G FG Monsanto Megan M MM Firouzi Fareheh F Echeagaray Oscar H OH Kim Taeyong T Adamson Robert M RM Dembitsky Walter P WP Gustafsson Åsa B ÅB Sussman Mark A MA

Stem cells (Dayton, Ohio) 20190130 4

Senescence-associated dysfunction deleteriously affects biological activities 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 characteristics 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 ...[more]

PMID: 30629785

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Project description:BackgroundIt is well known that muscle disuse atrophy is associated with mitochondrial dysfunction, which is implicated in reduced nicotinamide adenine dinucleotide (NAD+ ) levels. Nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in NAD+ biosynthesis, may serve as a novel strategy to treat muscle disuse atrophy by reversing mitochondrial dysfunction.MethodsTo investigate the effects of NAMPT on the prevention of disuse atrophy of skeletal muscles predominantly composed of slow-twitch (type I) or fast-twitch (type II) fibres, rabbit models of rotator cuff tear-induced supraspinatus muscle atrophy and anterior cruciate ligament (ACL) transection-induced extensor digitorum longus (EDL) atrophy were established and then administered NAMPT therapy. Muscle mass, fibre cross-sectional area (CSA), fibre type, fatty infiltration, western blot, and mitochondrial function were assayed to analyse the effects and molecular mechanisms of NAMPT in preventing muscle disuse atrophy.ResultsAcute disuse of the supraspinatus muscle exhibited significant loss of mass (8.86 ± 0.25 to 5.10 ± 0.79 g; P < 0.001) and decreased fibre CSA (3939.6 ± 136.1 to 2773.4 ± 217.6 μm2 , P < 0.001), which were reversed by NAMPT (muscle mass 6.17 ± 0.54 g, P = 0.0033; fibre CSA, 3219.8 ± 289.4 μm2 , P = 0.0018). Disuse-induced impairment of mitochondrial function were significantly improved by NAMPT, including citrate synthase activity (40.8 ± 6.3 to 50.5 ± 5.6 nmol/min/mg, P = 0.0043), and NAD+ biosynthesis (279.9 ± 48.7 to 392.2 ± 43.2 pmol/mg, P = 0.0023). Western blot revealed that NAMPT increases NAD+ levels by activating NAMPT-dependent NAD+ salvage synthesis pathway. In supraspinatus muscle atrophy due to chronic disuse, a combination of NAMPT injection and repair surgery was more effective than repair in reversing muscle atrophy. Although the predominant composition of EDL muscle is fast-twitch (type II) fibre type that differ from supraspinatus muscle, its mitochondrial function and NAD+ levels are also susceptible to disuse. Similar to the supraspinatus muscle, NAMPT-elevated NAD+ biosynthesis was also efficient in preventing EDL disuse atrophy by reversing mitochondrial dysfunction.ConclusionsNAMPT-elevated NAD+ biosynthesis can prevent disuse atrophy of skeletal muscles that predominantly composed with either slow-twitch (type I) or fast-twitch (type II) fibres by reversing mitochondrial dysfunction.

Dataset Information

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

Publications

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

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