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

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.

Glial Cells as Therapeutic Approaches in Brain Ischemia-Reperfusion Injury

“…Other studies support the idea that the balance between both activated phenotypes could determine the neurodegenerative disease progression, so that a majority of the M1 population is associated with a worse clinical prognosis [ 36 ]. Interestingly, activated microglia are known to switch from one profile to another and a great number of therapies are focused on this property [ 37 , 38 , 39 ]. M1 activated microglia contribute to an increase in the inflammation and cytotoxicity levels through the release of the cytokines TNF-α and IFN-γ; interleukins such as IL-1β, IL-6, IL-15, IL-18, and IL-23; chemokines like CCL2 and CXCL10; the metalloproteinases (MMPs) MMP-3 and MMP-9; and reactive oxygen/nitrogen species (ROS/RNS) [ 40 , 41 ].…”

Mechanisms of Macrophage Plasticity in the Tumor Environment: Manipulating Activation State to Improve Outcomes

“…However, instead of promoting the re-growth of tissue resident cells, these factors drive tumor growth. Likewise, macrophages also secrete key effectors of vascularization, like the vascular endothelial growth factor (VEGF) (42,43), plateletderived growth factor (PDGF) (44) and transforming growth factor b (TGFb) (45) to promote angiogenesis (Figure 1). These physiologic processes are hijacked to increase blood flow to the tumor, increasing tumor cell access to oxygen and nutrients for continued cell proliferation.…”

“…Conversely, the presence of M2 pro-wound healing macrophages in tumors is generally a negative prognostic marker, with patients with high numbers of intra-tumoral M2 macrophages showing decreased survival (67). Tumor cells are known to secrete, or induce the secretion of, factors like IL-4, IL-10 or IL-13 that polarize macrophages toward an M2 phenotype (44,68). Some pro-wound healing properties of M2 macrophages foster tumor growth and prepare a tumor-friendly milieu (Figure 1).…”

Oxidative Stress, Inflammation, and Autophagy: Potential Targets of Mesenchymal Stem Cells-Based Therapies in Ischemic Stroke

“…This research suggested that Ly6C+ cells may consist of heterogeneous populations in the infarct area, which can be modulated by intravenously infused allogeneic MSCs. Meanwhile, that BMSCs inactivated the microglia and induced M2 polarization was further observed by other researchers (Li et al, 2019d;Yang et al, 2020c). Oh et al (2018) demonstrated that human umbilical cord mesenchymal stem cells (hUMSCs) could relieve neuroinflammation in rodent stroke models by increasing interleukin-1 receptor antagonist (IL-1ra) expression in macrophage cell lines.…”