Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling  

作　　者：Fan Yang Wen-Bin Li Ye-Wei Qu Jin-Xing Gao Yu-Shi Tang Dong-Jie Wang Yu-Jun Pan 

机构地区：[1]Department of Neurology,The First Clinical College of Harbin Medical University,Harbin 150001,Heilongjiang Province,China [2]Department of Respiratory Medicine,The First Clinical College of Harbin Medical University,Harbin 150001,Heilongjiang Province,China

出　　处：《World Journal of Stem Cells》2020年第7期633-657,共25页世界干细胞杂志（英文版）（电子版）

摘　　要：BACKGROUND Bone marrow mesenchymal stem cells(BMSCs)are capable of shifting the microglia/macrophages phenotype from M1 to M2,contributing to BMSCsinduced brain repair.However,the regulatory mechanism of BMSCs on microglia/macrophages after ischemic stroke is unclear.Recent evidence suggests that mesencephalic astrocyte-derived neurotrophic factor(MANF)and plateletderived growth factor-AA(PDGF-AA)/MANF signaling regulate M1/M2 macrophage polarization.AIM To investigate whether and how MANF or PDGF-AA/MANF signaling influences BMSCs-mediated M2 polarization.METHODS We identified the secretion of MANF by BMSCs and developed transgenic BMSCs using a targeting small interfering RNA for knockdown of MANF expression.Using a rat middle cerebral artery occlusion(MCAO)model transplanted by BMSCs and BMSCs-microglia Transwell coculture system,the effect of BMSCsinduced downregulation of MANF expression on the phenotype of microglia/macrophages was tested by Western blot,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence.Additionally,microglia were transfected with mimics of miR-30a*,which inuenced expression of X-box binding protein(XBP)1,a key transcription factor that synergized with activating transcription factor 6(ATF6)to govern MANF expression.We examined the levels of miR-30a*,ATF6,XBP1,and MANF after PDGF-AA treatment in the activated microglia.RESULTS Inhibition of MANF attenuated BMSCs-induced functional recovery and decreased M2 marker production,but increased M1 marker expression in vivo or in vitro.Furthermore,PDGF-AA treatment decreased miR-30a*expression,had no influence on the levels of ATF6,but enhanced expression of both XBP1 and MANF.CONCLUSION BMSCs-mediated MANF paracrine signaling,in particular the PDGF-AA/miR-30a*/XBP1/MANF pathway,synergistically mediates BMSCs-induced M2 polarization.

关 键 词：Mesencephalic astrocyte-derived neurotrophic factor Bone marrow mesenchymal stem cell Microglia/macrophage polarization Endoplasmic reticulum stress Cerebral ischemia/reperfusion injury 

分 类 号：R743.3[医药卫生—神经病学与精神病学]