M2 macrophages promote vasculogenesis during retinal neovascularization by regulating bone marrow-derived cells via SDF-1/VEGF

• Published in: Cell and tissue research 2020-06, Vol.380 (3), p.469-486
• Main Authors: Wang, Yafen, Chang, Tianfang, Wu, Tong, Xu, Wenqin, Dou, Guorui, Wang, Yusheng, Guo, Changmei
• Format: Article
• Language: English
• Subjects: Actin; Animals; Biomedical and Life Sciences; Biomedicine; Bone marrow; Cell Differentiation; Cell Movement; Cells, Cultured; Chemokine CXCL12 - metabolism; Comparative analysis; Endothelial cells; Ethylenediaminetetraacetic acid; Green fluorescent protein; Human Genetics; Leukocyte migration; Macrophages; Macrophages - cytology; Mesenchymal Stem Cells - cytology; Mesenchyme; Mice; Mice, Inbred C57BL; Molecular Medicine; Neovascularization; Proteomics; Regular Article; Retina; Retinal Neovascularization - metabolism; SDF-1 protein; Signal transduction; Smooth muscle; Stem cells; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascularization
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-019-03166-9

Macrophages promote vasculogenesis during retinal neovascularization (RNV) by increasing the recruitment and differentiation of bone marrow-derived cells (BMCs). Different subtypes of macrophages (M1 and M2 macrophages) are associated with RNV. However, the mechanism underlying the regulation of BMCs by different macrophage subtypes during RNV remains unclear. In the present study, we investigated the role and mechanism of action of different macrophage subtypes that regulate BMCs during the development of RNV. The retinal avascular area and neovascularization (NV) tuft area in M2 macrophage group in vivo were the largest compared to those in the control phosphate buffer saline (PBS), unpolarized-M0, and M1 macrophage groups. The number of recruited green fluorescent protein (GFP)-positive BMCs and the degree of differentiation of BMCs into CD31-positive endothelial cells (ECs) and alpha-smooth muscle actin (α-SMA)-positive smooth muscle cells (SMCs) were higher in the M2 macrophage group than in the other groups. M2-conditional medium (M2-CM) affected the in vitro migration and activation of bone marrow mesenchymal stem cells (BMSCs, a subset of BMCs) more than M1-CM. The expression of stromal cell-derived factor-1 (SDF-1) and vascular endothelial growth factor (VEGF) in M2 macrophages and BMSCs cultured with M2-CM was also higher than that in M1 macrophages and BMSCs cultured with M1-CM. Migration of BMSCs was reduced after inhibiting the SDF-1 signaling pathway. Our results indicate that M2 macrophages may express significantly higher levels of SDF-1 and VEGF than M1 macrophages, thus regulating the recruitment and differentiation of BMCs and further aggravating vasculogenesis during RNV.