title: Human umbilical cord-derived mesenchymal stem cells elicit macrophages into an anti-inflammatory phenotype to alleviate insulin resistance in type 2 diabetic rats.
abstract: Insulin resistance, a major characteristic of type 2 diabetes (T2D), is closely associated with adipose tissue macrophages (ATMs) that induce chronic low-grade inflammation. Recently, mesenchymal stem cells (MSCs) have been identified in alleviation of insulin resistance. However, the underlying mechanism still remains elusive. Thus, we aimed to investigate whether the effect of MSCs on insulin resistance was related to macrophages phenotypes in adipose tissues of T2D rats. In this study, human umbilical cord-derived MSCs (UC-MSCs) infusion produced significantly anti-diabetic effects and promoted insulin sensitivity in T2D rats that were induced by a high-fat diet combined with streptozotocin and directed ATMs into an alternatively activated phenotype (M2, anti-inflammatory). In vitro, MSC-induced M2 macrophages alleviated insulin resistance caused by classically activated macrophages (M1, pro-inflammatory). Further analysis showed that M1 stimulated UC-MSCs to increase expression of interleukin (IL)-6, a molecule which upregulated IL4R expression, promoted phosphorylation of STAT6 in macrophages, and eventually polarized macrophages into M2 phenotype. Moreover, the UC-MSCs effect on macrophages was largely abrogated by small interfering RNA (siRNA) knockdown of IL-6. Together, our results indicate that UC-MSCs can alleviate insulin resistance in part via production of IL-6 that elicits M2 polarization. Additionally, human obesity and insulin resistance were associated with increased pro-inflammatory ATMs infiltration. Thus, MSCs may be a new treatment for obesity-related insulin resistance and T2D concerning macrophage polarized effects.
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.|School of Medicine, Nankai University, Tianjin, China.
authors.forename: Zongyan
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Institute of Basic Medicine Science, College of Life Science, Chinese PLA General Hospital, Beijing, China.
authors.forename: Haojie
authors.initials: H
authors.lastname: Hao
authors.affiliation: Institute of Basic Medicine Science, College of Life Science, Chinese PLA General Hospital, Beijing, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Tong
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Institute of Basic Medicine Science, College of Life Science, Chinese PLA General Hospital, Beijing, China.
authors.forename: Jiejie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, Chinese PLA 309 Hospital, Beijing, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Pang
authors.affiliation: Institute of Basic Medicine Science, College of Life Science, Chinese PLA General Hospital, Beijing, China.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Si
authors.affiliation: Department of General surgery, Chinese PLA General Hospital, Beijing, China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zang
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Mu
authors.affiliation: Institute of Basic Medicine Science, College of Life Science, Chinese PLA General Hospital, Beijing, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Han
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000637:transplantation; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000628:therapy*; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000628:therapy*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000628:therapy; D007333:Insulin Resistance / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology; D009765:Obesity / Q000473:pathology / Q000628:therapy*; D010641:Phenotype; D051381:Rats; D014470:Umbilical Cord / Q000166:cytology / Q000637:transplantation
chemical_list: D015850:Interleukin-6
keywords: Insulin resistance; Macrophages; Mesenchymal stem cells; Type 2 diabetes mellitus