J Appl Biomed 13:263-271, 2015 | DOI: 10.1016/j.jab.2015.06.002

Depletion of androgen receptor (AR) in mesenchymal stem cells (MSCs) inhibits induction of CD4+CD25+FOX3+ regulatory T (Treg) cells via androgen TGF-β interaction

Abdullah Alawad^a, Saleh Altuwaijri^b,h, Ahmed Aljarbu^c, Ilona Kryczek^b, Yuanjie Niu^d,e, Fahd A. Al-sobayil^f, Chawnshang Chang^d, Ali Bayoumi^g, Weiping Zou^b, Volker Rudat^g, Mohamed Hammad^a,h,*

^a National Center for Stem Cell Technology (NCSCT), Life Sciences and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh 11442, Saudi Arabia

^b Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA

^c College of Applied Medical Sciences, Qassim University, Qassim, Saudi Arabia

^d George Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, NY 14642, USA

^e Sex Hormone Research Center, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China

^f Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia

^g Saud Al-Babtain Cardiac Center, Eastern Province, Dammam 31463, Saudi Arabia

^h SAAD Research & Development Center, Clinical Research Lab. & Radiation Oncology, SAAD Specialist Hospital, P.O. Box 30353, Al Khobar 31952, Saudi Arabia

MSCs produce CD4(+)CD25(+)FOX3(+) regulatory T (Treg) cells from activated peripheral blood mononuclear cells (PBMC), T-CD4+ and T-CD8+ cells in vitro and in vivo. Here we investigated whether the deficiency of androgen/AR in MSCs influence Treg induction from total PBMC, splenocytes, CD4+CD25-through AR/TGF-β interaction. Eight to 12-week-old wild type and general androgen receptor knockout (ARKO) mice were used. MSCs were collected, characterized and function of Treg cells was studied. Our result showed that depletion of AR suppressed the immunosuppressive effect of MSCs, and demonstrated that WT-MSC-induced Treg cell expansion was partially impaired by blocking androgen receptor signal. Furthermore, the levels of TGF-β were lower in the T cell coculture with ARKO-MSC compared to WT-MSC. Exposure of ARKO-MSC cells to exogenous active TGF-β partially restored the induction of Treg cell expansion by ARKO-MSC cells. Our data suggest that ARKO-MSC hampers Treg cell expansion and function via androgen/AR and TGF-β signal pathways interaction. To the best of our knowledge, this study is the first investigating the interaction of MSCs from ARKO mice and WT Tregs in an allogeneic co-culture model. Together, these results might provide great insight into treatment of inflammatory and autoimmune diseases.

Keywords: Mesenchymal stem cells; Androgen receptor; Regulatory T (Treg) cells; TGF-β; CD4+FOXP3+ T cells; Casodex

Received: March 16, 2015; Revised: June 3, 2015; Accepted: June 5, 2015; Published: November 1, 2015  Show citation