Fig. 2

Mechanism by which MSCs regulate macrophage polarization in the context of SCI. MSCs can promote the polarization of macrophages at the site of SCI by secreting soluble proteins including IL-4, IL-13, PACAP, CCL2, CCL5, and ED-Siglec-9. IL-4 can activate the JNK, JAK/STAT6, and PI3K signal pathways through IL-4R, and ultimately promote the expression of M2 related genes. In turn, IL-13 activates IL-10R, thereby participating in the process by acting on STAT6. In addition, CCL5 can induce high levels of IL-4 by acting on CCL5R, thereby promoting M2 polarization of macrophages. CCL2 can induce the expression of MCPIP through CCR2, thereby activating C/EBPβ, PPARγ, and inhibiting NF-κB to exert anti-inflammatory effects. ED-Siglec-9 also works synergistically with CCR2. Regarding PACAP, its mechanism of action is not yet clear. Furthermore, MSCs-exo can also play a similar role, by carrying MiR-216a-5p and lncRNAs Gm37494, which will inhibit TLR4/NF-κB and activate PI3K/AKT signaling pathway, and downregulate the expression of MiR-130b-3p and upregulate the expression of PPARγ, respectively, hence, inhibiting M1 and enhancing M2 marker expression. Lastly, MSCs can improve the inflammatory environment of the SCI site and relieve its manifestations. AKT, protein kinase B; CCL, chemokine (C-C motif) ligand; CCR, chemokine (C-C motif) receptor; C/EBPβ, CCAAT/enhancer-binding protein beta; ED-Siglec-9, ectodomain of sialic acid-binding Ig-like lectin-9; IL, interleukin; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; lncRNAs, long non-coding RNAs; MCPIP, monocyte chemoattractant protein-1-induced protein.; MSCs, mesenchymal stem cells; NF-κB, nuclear factor kappa-B; PACAP, pituitary adenylate cyclase-activating polypeptide; PI3K, phosphoinositide 3-kinase; PPARβ, peroxisome-proliferator-activated receptor β; SCI, spinal cord injury; TLR, Toll-like receptor