Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Jul 26, 2020; 12(7): 633-658
Published online Jul 26, 2020. doi: 10.4252/wjsc.v12.i7.633
Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling
Fan Yang, Wen-Bin Li, Ye-Wei Qu, Jin-Xing Gao, Yu-Shi Tang, Dong-Jie Wang, Yu-Jun Pan
Fan Yang, Wen-Bin Li, Ye-Wei Qu, Jin-Xing Gao, Yu-Shi Tang, Yu-Jun Pan, Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
Dong-Jie Wang, Department of Respiratory Medicine, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
Author contributions: Yang F and Pan YJ performed study design and wrote the paper; Yang F, Li WB, Qu YW, and Gao JX performed the experiments and analyzed the results; Tang YS and Wang DJ contributed to the preparation of samples.
Supported by the State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, No. SKLN-201402 and No. SKLN-201801; and the Foundation for Returned Overseas Chinese Scholars of Heilongjiang Province, No. LC201040.
Institutional animal care and use committee statement: The study was approved by the Ethics Committee of the First Clinical College of Harbin Medical University.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Yu-Jun Pan, PhD, Professor, Chief Doctor, Department of Neurology, The First Clinical College of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China. yujunpan@ems.hrbmu.edu.cn
Received: January 20, 2020
Peer-review started: January 20, 2020
First decision: March 24, 2020
Revised: April 4, 2020
Accepted: May 15, 2020
Article in press: May 15, 2020
Published online: July 26, 2020
Processing time: 187 Days and 20.4 Hours
Abstract
BACKGROUND

Bone marrow mesenchymal stem cells (BMSCs) are capable of shifting the microglia/macrophages phenotype from M1 to M2, contributing to BMSCs-induced 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 platelet-derived 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 BMSCs-induced 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 influenced 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.

Keywords: Mesencephalic astrocyte–derived neurotrophic factor; Bone marrow mesenchymal stem cell; Microglia/macrophage polarization; Endoplasmic reticulum stress; Cerebral ischemia/reperfusion injury

Core tip: Induction of M2 microglia/macrophage polarization may contribute to the mechanisms underlying the neuroprotective effect of bone marrow mesenchymal stem cells (BMSCs) in treating stroke. This is one of the few known studies exploring the soluble mediators responsible for interactions between BMSCs and microglia/macrophages. We demonstrated that BMSCs-mediated MANF paracrine signaling, in particular the PDGF-AA/miR-30a*/XBP1/MANF pathway, was involved in BMSCs-induced M2 phenotype polarization. Therefore, this novel molecular mechanism of BMSCs-based immunomodulatory effect on microglia/macrophages may be a novel promising therapeutic strategy for treatment of ischemic stroke.