Protection of mitochondrial genome integrity: A new stem cell property?

Alison, Malcolm R.; McDonald, Stuart; Lin, Wei-Che; Wright, Nicholas

doi:10.1002/hep.23171

Cited by 2 publications

(1 citation statement)

References 22 publications

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“…Here, mtDNA copies from BM‐MSCs cultured in hypoxia seemed to less accumulate damage that might hinder their amplifications, resulting in greater mtDNA stability. Thus, reproducing at least partially the stem cell niche might be of interest for the efficient repair of mtDNA lesions . Accordingly, hypoxia would limit the emergence and the propagation of mtDNA defects toward daughter or surrounding cells and particularly delay aging of BM‐MSCs .…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Differentially Modulates the Genomic Stability of Clinical-Grade ADSCs and BM-MSCs in Long-Term Culture

et al. 2015

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Long-term cultures under hypoxic conditions have been demonstrated to maintain the phenotype of mesenchymal stromal/stem cells (MSCs) and to prevent the emergence of senescence. According to several studies, hypoxia has frequently been reported to drive genomic instability in cancer cells and in MSCs by hindering the DNA damage response and DNA repair. Thus, we evaluated the occurrence of DNA damage and repair events during the ex vivo expansion of clinical-grade adipose-derived stromal cells (ADSCs) and bone marrow (BM)-derived MSCs cultured with platelet lysate under 21% (normoxia) or 1% (hypoxia) O 2 conditions. Hypoxia did not impair cell survival after DNA damage, regardless of MSC origin. However, ADSCs, unlike BMMSCs, displayed altered cH2AX signaling and increased ubiquitylated cH2AX levels under hypoxic conditions, indicating an impaired resolution of DNA damage-induced foci. Moreover, hypoxia specifically promoted BM-MSC DNA integrity, with increased Ku80, TP53BP1, BRCA1, and RAD51 expression levels and more efficient nonhomologous end joining and homologous recombination repair. We further observed that hypoxia favored mtDNA stability and maintenance of differentiation potential after genotoxic stress. We conclude that long-term cultures under 1% O 2 were more suitable for BM-MSCs as suggested by improved genomic stability compared with ADSCs. STEM CELLS 2015;33:3608-3620 SIGNIFICANCE STATEMENTHuman mesenchymal stem cells (MSCs) feature differentiation capacities, immunomodulatory properties and therefore represent a great potential for medicine. In vitro culture allows their amplification for suitable clinical uses. Hypoxia seems relevant for the prevention of senescence and loss of MSC features. However, hypoxia is shown to promote cancer or DNA damage response (DDR) and repair failures. We demonstrate that long-term culture of MSCs with platelet lysate in hypoxia does not necessarily inhibit DDR and DNA repair. Here, bone marrowMSCs conserved or rather improved their DDR and DNA repair (NHEJ, HR), mtDNA stability in hypoxia compared to adipose-derived stem cells. Moreover, the ubiquitylation status of gH2AX between BM-MSCs and ADSCs might be responsible for changes in their DNA repair activities. Appropriate oxygen tension seems crucial to preserve the MSCs genomic stability according to their origins.

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Section: Discussionmentioning

confidence: 99%

Hypoxia Differentially Modulates the Genomic Stability of Clinical-Grade ADSCs and BM-MSCs in Long-Term Culture

et al. 2015

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Impact of hypoxia and long-term cultivation on the genomic stability and mitochondrial performance of ex vivo expanded human stem/stromal cells

et al. 2012

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Recent studies have described the occurrence of chromosomal abnormalities and mitochondrial dysfunction in human stem/stromal cells (SCs), particularly after extensive passaging in vitro and/or expansion under low oxygen tensions. To deepen this knowledge we investigated the influence of hypoxia (2% O(2)) and prolonged passaging (>P10) of human bone marrow stromal cells (BMSCs) and adipose-derived stromal cells (ASCs) on the expression of genes involved in DNA repair and cell-cycle regulation pathways, as well as on the occurrence of microsatellite instability and changes in telomere length. Our results show that hypoxic conditions induce an immediate and concerted down-regulation of genes involved in DNA repair and damage response pathways (MLH1, RAD51, BRCA1, and Ku80), concomitantly with the occurrence of microsatellite instability while maintaining telomere length. We further searched for mutations occurring in the mitochondrial genome, and monitored changes in intracellular ATP content, membrane potential and mitochondrial DNA content. Hypoxia led to a simultaneous decrease in ATP content and in the number of mitochondrial genomes, whereas the opposite effect was observed after prolonged passaging. Moreover, we show that neither hypoxia nor prolonged passaging significantly affected the integrity of the mitochondrial genome. Ultimately, we present evidence on how hypoxia selectively impacts the cellular response of BMSCs and ASCs, thus pointing for the need to optimize oxygen tension according to the cell source.

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Protection of mitochondrial genome integrity: A new stem cell property?

Cited by 2 publications

References 22 publications

Hypoxia Differentially Modulates the Genomic Stability of Clinical-Grade ADSCs and BM-MSCs in Long-Term Culture

Hypoxia Differentially Modulates the Genomic Stability of Clinical-Grade ADSCs and BM-MSCs in Long-Term Culture

Impact of hypoxia and long-term cultivation on the genomic stability and mitochondrial performance of ex vivo expanded human stem/stromal cells

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