c-Maf regulates pluripotency genes, proliferation/self-renewal, and lineage commitment in ROS-mediated senescence of human mesenchymal stem cells

Abstract

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.

Oxidative stress induces imbalance of adipogenic/osteoblastic lineage commitment in mesenchymal stem cells through decreasing SIRT1 functions

“…5). In addition to our laboratory's and others' work demonstrating how ROS and cellular senescence decrease the expression of c-MAF, a cofactor of RUNX2 [17,33], this study adds to the molecular understanding on how ROS and oxidative stress adversely impact on osteogenesis. Collectively, these reports highlight the importance of decreasing oxidative stress and ROS-levels which correlate strongly with age-for MSC osteogenesis to occur.…”

“…2A). Conversely, expression levels of committed osteogenic genes such as collagen type 1a1 (COL1A1) [32] and the RUNX2 coactivator c-MAF [17,33] were decreased in C3H MSCs cultured in OM with exogenous H 2 O 2 treatment ( Fig. 2A).…”

Impact of Mediterranean diet on metabolic syndrome, cancer and longevity

“…A large number of studies have evaluated the ROS in cancer cells [185–196] and their relationship with the mitochondrial activity [197–208]. …”

Regulation of the mitochondrial reactive oxygen species: Strategies to control mesenchymal stem cell fates ex vivo and in vivo

“…Moreover, although Li et al demonstrated that MSCs derived from old donors showed a more rapidly decreased survival rate than MSCs derived from young donors in the infarct region in acute myocardial infarction (MI) model, N‐acetyl‐L‐cysteine (NAC) which is a ROS scavenger can protected MSCs derived from old donors from apoptosis in vivo and significantly enhanced the therapeutic effects of MSCs. Long‐term culture always results in proliferative decline, cell cycle arrest and decreased differentiation capacity in adipose‐derived MSCs by ROS‐induced suppression of c‐Maf . However, long‐term culture of umbilical cord blood‐derived MSCs reinforces senescence by activating p38, MAPK, and p53/p21 pathways and enhancing ROS generation .…”

“…Various conditions including ageing, long-term culture and H 2 O 2 , adverse oxygen content, high glucose, proinflammatory cytokines and other toxic factors, abnormally up-regulated ROS production can harm MSC activities. 22,[29][30][31][32][33] On the other hand, although MSCs play critical roles on immunomodulatory properties for therapy in various diseases, the constant isolation from donors also bring out unrecoverable injury. 34…”