c-Maf regulates pluripotency genes, proliferation/self-renewal, and lineage commitment in ROS-mediated senescence of human mesenchymal stem cells.
Mesenchymal stem cells (MSCs) are therapeutically relevant multilineage and immunomodulatory progenitors. Ex vivo expansion of these rare cells is necessary for clinical application and can result in detrimental senescent effects, with mechanisms still largely unknown. We found that vigorous ex vivo expansion of human adipose tissue-derived MSCs (hAMSCs) results in proliferative decline, cell cycle arrest, and altered differentiation capacity. This senescent phenotype was associated with reactive oxygen species (ROS) accumulation, and with increased expression of G1 cell -cycle inhibitors- p15INK4b and p16INK4a - but decreased expression of pluripotency genes-Oct-4, Sox-2, Nanog, and c-Myc-as well as c-Maf a co-factor of MSC lineage-specific transcription factor and sensitive to oxidative stress. These global changes in the transcriptional and functional programs of proliferation, differentiation, and self-renewal were all mediated by ROS-induced suppression of c-Maf, as evidenced by binding of c-Maf to promoter regions of multiple relevant genes in hAMSCs which could be reduced by exogenous ROS. Our findings implicate the strong effects of ROS on multiple stem cell functions with a central role for c-Maf in stem cell senescence.
Department of Obstetrics/Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Pei-Min
PM
Chen
Department of Obstetrics/Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chia-Hua
CH
Lin
Department of Obstetrics/Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Nan-Ting
NT
Li
Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.|Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Yao-Ming
YM
Wu
Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Medical Education & Bioethics, Graduate Institute of Medical Education & Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan.
Ming-Tsan
MT
Lin
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
Shih-Chieh
SC
Hung
Department of Obstetrics/Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.
Men-Luh
ML
Yen
D049109:Cell Proliferation / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
C495607:MAF protein, human; D051257:Proto-Oncogene Proteins c-maf; D017382:Reactive Oxygen Species
Gerotarget; ROS-mediated senescence; c-Maf; human adipose tissue-derived MSCs (hAMSCs); lineage commitment; self-renewal