PMID- 31426846 OWN - NLM STAT- MEDLINE DCOM- 20200713 LR - 20200713 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 10 IP - 1 DP - 2019 Aug 19 TI - Decitabine assists umbilical cord-derived mesenchymal stem cells in improving glucose homeostasis by modulating macrophage polarization in type 2 diabetic mice. PG - 259 LID - 10.1186/s13287-019-1338-2 [doi] LID - 259 AB - BACKGROUND: Mesenchymal stem cells (MSCs) have emerged as a promising therapy for type 2 diabetes (T2D). Mechanistic researches demonstrate that the anti-diabetic effect of MSCs is partially mediated by eliciting macrophages into an anti-inflammatory phenotype thus alleviating insulin resistance. However, single MSC infusion is insufficient to ameliorate sustained hyperglycemia or normalize blood glucose levels. In this study, we used decitabine (DAC), which is involved in the regulation of macrophage polarization, to test whether MSCs combined with decitabine can prolong and enhance the anti-diabetic effect in T2D mice. METHODS: High-fat diet (HFD) and streptozocin (STZ) were given to induce T2D mouse model. Successfully induced T2D mice were randomly divided into four groups: T2D group, MSC group, DAC group, and MSC + DAC group. Blood glucose was monitored, and glucose tolerance and insulin sensitivity were evaluated during the entire analysis period. Epididymal fat was extracted for analysis of macrophage phenotype and inflammation in adipose tissue. In vitro, we examined the effect of MSC + DAC on macrophage polarization in bone marrow-derived macrophages (BMDMs) and explore the possible mechanism. RESULTS: MSC infusion effectively improved insulin sensitivity and glucose homeostasis in T2D mice within 1 week, whereas combination therapy of MSCs + DAC extended the anti-diabetic effects of MSCs from 1 to 4 weeks (the end of the observation). Correspondingly, more M2 macrophages in adipose tissue were observed in the combination therapy group over the entire study period. In vitro, compared with the MSC group, MSCs combined with decitabine more effectively polarized M1 macrophages to M2 macrophages. Further analysis showed that the effect of MSC + DAC on macrophage polarization was largely abrogated by the peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist GW9662. CONCLUSIONS: Our data suggest that MSCs combined with decitabine can more effectively alleviate insulin resistance and prolong and enhance the anti-diabetic effect of MSCs in T2D mice in part by prompting M2 polarization in a PPARgamma-dependent manner. Thus, decitabine may be an applicable addition to MSCs for diabetes therapy. UC-MSCs combined with decitabine activate the IL4R/STAT6/STAT3/PPARgamma axis to further promote M2 macrophage polarization in adipose tissue, reduce inflammation, improve insulin sensitivity, and lead to better glucose metabolism and long-term hypoglycemic effects. FAU - Gao, Jieqing AU - Gao J AD - Department of Endocrinology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China. AD - Department of Endocrinology, Beijing Rehabilitation Hospital of Capital Medical University, Beijing, China. FAU - Cheng, Yu AU - Cheng Y AD - Department of Endocrinology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China. FAU - Hao, Haojie AU - Hao H AD - Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, Chinese PLA General Hospital, Beijing, China. FAU - Yin, Yaqi AU - Yin Y AD - Department of Endocrinology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China. FAU - Xue, Jing AU - Xue J AD - Department of Endocrinology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China. FAU - Zhang, Qi AU - Zhang Q AD - Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. FAU - Li, Lin AU - Li L AD - Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China. FAU - Liu, Jiejie AU - Liu J AD - Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, Chinese PLA General Hospital, Beijing, China. FAU - Xie, Zongyan AU - Xie Z AD - Department of Geriatrics, China-Japan Friendship Hospital, Beijing, China. FAU - Yu, Songyan AU - Yu S AD - Department of Endocrinology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China. FAU - Li, Bing AU - Li B AD - Department of Endocrinology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China. FAU - Han, Weidong AU - Han W AD - Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, Chinese PLA General Hospital, Beijing, China. FAU - Mu, Yiming AU - Mu Y AUID- ORCID: 0000-0002-3344-3540 AD - Department of Endocrinology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China. muyiming@301hospital.com.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190819 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Blood Glucose) RN - 0 (Insulin) RN - 776B62CQ27 (Decitabine) SB - IM MH - Animals MH - Antimetabolites, Antineoplastic/pharmacology MH - Blood Glucose/*metabolism MH - Decitabine/*pharmacology MH - Diabetes Mellitus, Experimental/etiology/metabolism/*therapy MH - Diabetes Mellitus, Type 2/etiology/metabolism/*therapy MH - Diet, High-Fat/adverse effects MH - Inflammation/metabolism/pathology/therapy MH - Insulin/metabolism MH - *Macrophage Activation MH - Male MH - Mesenchymal Stem Cell Transplantation/*methods MH - Mesenchymal Stem Cells/*cytology MH - Mice MH - Mice, Inbred C57BL MH - Umbilical Cord/*cytology PMC - PMC6700792 OTO - NOTNLM OT - Decitabine OT - Diabetes OT - Insulin resistance OT - Macrophage polarization OT - Mesenchymal stem cells COIS- The authors declare that they have no competing interests. EDAT- 2019/08/21 06:00 MHDA- 2020/07/14 06:00 PMCR- 2019/08/19 CRDT- 2019/08/21 06:00 PHST- 2019/02/25 00:00 [received] PHST- 2019/07/14 00:00 [accepted] PHST- 2019/07/04 00:00 [revised] PHST- 2019/08/21 06:00 [entrez] PHST- 2019/08/21 06:00 [pubmed] PHST- 2020/07/14 06:00 [medline] PHST- 2019/08/19 00:00 [pmc-release] AID - 10.1186/s13287-019-1338-2 [pii] AID - 1338 [pii] AID - 10.1186/s13287-019-1338-2 [doi] PST - epublish SO - Stem Cell Res Ther. 2019 Aug 19;10(1):259. doi: 10.1186/s13287-019-1338-2.