Published online Jul 26, 2020. doi: 10.4252/wjsc.v12.i7.633
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
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.
To investigate whether and how MANF or PDGF-AA/MANF signaling influences BMSCs-mediated M2 polarization.
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.
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.
BMSCs-mediated MANF paracrine signaling, in particular the PDGF-AA/miR-30a*/XBP1/MANF pathway, synergistically mediates BMSCs-induced M2 polarization.
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.