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C-C chemokine receptor type 2-overexpressing exosomes alleviated experimental post-stroke cognitive impairment by enhancing microglia/macrophage M2 polarization

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World Journal of Stem Cells 2020年第2期12卷 152-167页

作者： Huai-Chun Yang Min Zhang Rui Wu Hai-Qing Zheng Li-Ying Zhang Jing Luo Li-Li Li Xi-Quan Hu Department of Rehabilitation Medicine the Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510000Guangdong ProvinceChina Department of Andrology the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510000Guangdong ProvinceChina

BACKGROUND Human-derived mesenchymal stromal cells have been shown to improve cognitive function following experimental *** activity of exosomes has been verified to be comparable to the therapeutic effects of mesenchymal stromal ***,the effects of exosomes derived from human umbilical cord mesenchymal stem cells(HUC-MSCs)(ExoCtrl)on post-stroke cognitive impairment(PSCI)have rarely been ***,whether exosomes derived from C-C chemokine receptor type 2(CCR2)-overexpressing HUC-MSCs(ExoCCR2)can enhance the therapeutic effects on PSCI and the possible underlying mechanisms have not been *** To investigate the effects of ExoCtrl on PSCI and whether ExoCCR2 can enhance therapeutic effects on *** Transmission electron microscopy,qNano®particles analyzer,and Western blotting were employed to determine the morphology and CCR2 expression of ExoCtrl or *** was used to study the binding capacity of exosomes to CC chemokine ligand 2(CCL2)in *** the intravenous injection of ExoCtrl or ExoCCR2 into experimental rats,the effect of ExoCtrl and ExoCCR2 on PSCI was assessed by Morris water *** and oligodendrogenesis were analyzed by Western blotting and immunofluorescence ***-PCR and immunofluorescence microscopy were conducted to compare the microglia/macrophage *** infiltration and activation of hematogenous macrophages were analyzed by Western blotting and transwell migration *** CCR2-overexpressing HUC-MSCs loaded the CCR2 receptor into their *** morphology and diameter distribution between ExoCtrl and ExoCCR2 showed no significant ***2 bound significantly to CCL2 but ExoCtrl showed little CCL2 *** both ExoCCR2 and ExoCtrl showed beneficial effects on PSCI,oligodendrogenesis,remyelination,and microglia/macrophage polarization,ExoCCR2 exhibited a significantly superior beneficial *** also found that ExoCCR2 could suppress the

关键词： Cognitive impairment Stroke Exosomes C-C chemokine receptor type 2 microglia/macrophage polarization Remyelination

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

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World Journal of Stem Cells 2020年第7期12卷 633-657页

作者： Fan Yang Wen-Bin Li Ye-Wei Qu Jin-Xing Gao Yu-Shi Tang Dong-Jie Wang Yu-Jun Pan Department of Neurology The First Clinical College of Harbin Medical UniversityHarbin 150001Heilongjiang ProvinceChina Department of Respiratory Medicine The First Clinical College of Harbin Medical UniversityHarbin 150001Heilongjiang ProvinceChina

BACKGROUND Bone marrow mesenchymal stem cells(BMSCs)are capable of shifting the microglia/macrophages phenotype from M1 to M2,contributing to BMSCsinduced brain ***,the regulatory mechanism of BMSCs on microglia/macrophages after ischemic stroke is *** evidence suggests that mesencephalic astrocyte-derived neurotrophic factor(MANF)and plateletderived growth factor-AA(PDGF-AA)/MANF signaling regulate M1/M2 macrophage *** To investigate whether and how MANF or PDGF-AA/MANF signaling influences BMSCs-mediated M2 *** We identified the secretion of MANF by BMSCs and developed transgenic BMSCs using a targeting small interfering RNA for knockdown of MANF *** 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 ***,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 *** examined the levels of miR-30a*,ATF6,XBP1,and MANF after PDGF-AA treatment in the activated *** Inhibition of MANF attenuated BMSCs-induced functional recovery and decreased M2 marker production,but increased M1 marker expression in vivo or in ***,PDGF-AA treatment decreased miR-30a*expression,had no influence on the levels of ATF6,but enhanced expression of both XBP1 and *** 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

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