Oncotarget

Research Papers: Gerotarget (Focus on Aging):

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

Pei-Min Chen, Chia-Hua Lin, Nan-Ting Li, Yao-Ming Wu, Ming-Tsan Lin, Shih-Chieh Hung and Men-Luh Yen _

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Oncotarget. 2015; 6:35404-35418. https://doi.org/10.18632/oncotarget.6178

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Abstract

Pei-Min Chen1,*, Chia-Hua Lin1,*, Nan-Ting Li1, Yao-Ming Wu2,3, Ming-Tsan Lin3,4, Shih-Chieh Hung5,6 and Men-Luh Yen1,2

1 Department of Obstetrics/Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan

2 Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan

3 Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

4 Department of Medical Education & Bioethics, Graduate Institute of Medical Education & Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan

5 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

6 Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

* These authors have contributed equally to this manuscript

Correspondence to:

Men-Luh Yen, email:

Keywords: human adipose tissue-derived MSCs (hAMSCs), ROS-mediated senescence, c-Maf, self-renewal, lineage commitment, Gerotarget

Received: August 18, 2015 Accepted: October 06, 2015 Published: October 19, 2015

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.


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