PMID- 29287601 OWN - NLM STAT- MEDLINE DCOM- 20180806 LR - 20211204 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 8 IP - 1 DP - 2017 Dec 29 TI - mTOR inhibition improves the immunomodulatory properties of human bone marrow mesenchymal stem cells by inducing COX-2 and PGE(2). PG - 292 LID - 10.1186/s13287-017-0744-6 [doi] LID - 292 AB - BACKGROUND: Bone marrow mesenchymal stem cells (MSCs) are promising candidates for the treatment of various inflammatory disorders due to their profound immunomodulatory properties. However, the immunosuppressive capacity of MSCs needs activation by an inflammatory microenvironment, which may negatively impact the therapeutic effect because of increased immunogenicity. Here we explore the role of mammalian target of rapamycin (mTOR) signaling on the immunosuppressive capacity of MSCs, and its impact on immunogenicity in the inflammatory microenvironment. METHODS: Human bone marrow MSCs were cocultured with activated human peripheral blood mononuclear cells, CD4(+) T cells, and mouse splenocytes to evaluate the immunosuppressive function. Immunosuppressive factors were assessed by quantitative real-time polymerase chain reaction (PCR), Western blot, and enzyme-linked immunosorbent assay (ELISA). The expression of major histocompatibility complex (MHC) was detected by flow cytometry. Short hairpin (sh)RNA was used to downregulate tuberous sclerosis complex (TSC)2, TSC1, and cyclooxygenase (COX)-2 in MSCs. RESULTS: Inhibition of mTOR signaling using rapamycin enhanced the immunosuppressive functions of MSCs, while prolonged exposure to rapamycin did not. The enhancement of the immunosuppressive function was independent of the inflammatory microenvironment, and occurred mainly through the upregulation of COX-2 and prostaglandin-E(2) (PGE(2)) expression. Furthermore, mTOR inhibition did not impact the immunogenicity of MSCs. However, the upregulated expression of MHC class II molecules by interferon (IFN)-gamma was attenuated by mTOR inhibition, whereas TSC2 knockdown had the opposite effect. CONCLUSIONS: These results reveal that the mTOR signaling pathway regulates MSC immunobiology, and short-term exposure to rapamycin could be a novel approach to improve the MSC-based therapeutic effect. FAU - Wang, Binsheng AU - Wang B AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, People's Republic of China. AD - Institute of Hematology, Zhejiang University, Hangzhou, 310003, China. FAU - Lin, Yu AU - Lin Y AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, People's Republic of China. AD - Institute of Hematology, Zhejiang University, Hangzhou, 310003, China. FAU - Hu, Yongxian AU - Hu Y AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, People's Republic of China. AD - Institute of Hematology, Zhejiang University, Hangzhou, 310003, China. FAU - Shan, Wei AU - Shan W AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, People's Republic of China. AD - Institute of Hematology, Zhejiang University, Hangzhou, 310003, China. FAU - Liu, Senquan AU - Liu S AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, People's Republic of China. AD - Institute of Hematology, Zhejiang University, Hangzhou, 310003, China. FAU - Xu, Yulin AU - Xu Y AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, People's Republic of China. AD - Institute of Hematology, Zhejiang University, Hangzhou, 310003, China. FAU - Zhang, Hao AU - Zhang H AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, People's Republic of China. AD - Institute of Hematology, Zhejiang University, Hangzhou, 310003, China. FAU - Cai, Shuyang AU - Cai S AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, People's Republic of China. AD - Institute of Hematology, Zhejiang University, Hangzhou, 310003, China. FAU - Yu, Xiaohong AU - Yu X AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, People's Republic of China. AD - Institute of Hematology, Zhejiang University, Hangzhou, 310003, China. FAU - Cai, Zhen AU - Cai Z AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, People's Republic of China. AD - Institute of Hematology, Zhejiang University, Hangzhou, 310003, China. FAU - Huang, He AU - Huang H AUID- ORCID: 0000-0002-2723-1621 AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, People's Republic of China. huanghe@zju.edu.cn. AD - Institute of Hematology, Zhejiang University, Hangzhou, 310003, China. huanghe@zju.edu.cn. LA - eng GR - 2015CB964900/National Basic Research Program of China/International GR - 81520108002/Funds for International Cooperation and Exchange of the National Natural Science Foundation of China/International GR - 81600146/National Natural Science Foundation of China/International GR - 81470341/National Natural Science Foundation of China/International GR - 2015M581951/China Postdoctoral Science Foundation/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171229 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - K7Q1JQR04M (Dinoprostone) SB - IM MH - Animals MH - Cyclooxygenase 2/*metabolism MH - Dinoprostone/*metabolism MH - Humans MH - Immunomodulation/*immunology MH - Mesenchymal Stem Cells/cytology/*metabolism MH - Mice MH - Signal Transduction MH - TOR Serine-Threonine Kinases/*metabolism PMC - PMC5747167 OTO - NOTNLM OT - Immunogenicity OT - Immunosuppressive properties OT - Mesenchymal stem cells OT - Rapamycin OT - TSC-mTOR pathway COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All donors provided written informed consent in accordance with the Helsinki Declaration, and experiments were approved by the ethics committee of The First Affiliated Hospital of Zhejiang University (reference number 2016-82). The animal experiments were approved by the animal ethics committee of The First Affiliated Hospital of Zhejiang University (reference number 2016-116). CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2017/12/31 06:00 MHDA- 2018/08/07 06:00 PMCR- 2017/12/29 CRDT- 2017/12/31 06:00 PHST- 2017/10/19 00:00 [received] PHST- 2017/12/05 00:00 [accepted] PHST- 2017/11/22 00:00 [revised] PHST- 2017/12/31 06:00 [entrez] PHST- 2017/12/31 06:00 [pubmed] PHST- 2018/08/07 06:00 [medline] PHST- 2017/12/29 00:00 [pmc-release] AID - 10.1186/s13287-017-0744-6 [pii] AID - 744 [pii] AID - 10.1186/s13287-017-0744-6 [doi] PST - epublish SO - Stem Cell Res Ther. 2017 Dec 29;8(1):292. doi: 10.1186/s13287-017-0744-6.