Open AccessHypoxia Differentially Modulates the Genomic Stability of Clinical‐Grade ADSC s and BM‐MSC s in Long‐Term Culture
Author(s) -
Bigot Nicolas,
Mouche Audrey,
Preti Milena,
Loisel Séverine,
Renoud MarieLaure,
Le Guével Rémy,
Sensebé Luc,
Tarte Karin,
Pedeux Rémy
Publication year - 2015
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2195
Subject(s) - biology , mesenchymal stem cell , genome instability , dna damage , microbiology and biotechnology , dna repair , stromal cell , stem cell , rad51 , hypoxia (environmental) , homologous recombination , cancer research , immunology , genetics , dna , chemistry , organic chemistry , oxygen
Abstract 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 BM‐MSCs, displayed altered γH2AX signaling and increased ubiquitylated γH2AX 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. S tem C ells 2015;33:3608–3620