Bone marrow-derived cells in ocular neovascularization: contribution and mechanisms

Abstract

Ocular neovascularization often leads to severe vision loss. The role of bone marrow-derived cells (BMCs) in the development of ocular neovascularization, and its significance, is increasingly being recognized. In this review, we discuss their contribution and the potential mechanisms that mediate the effect of BMCs on the progression of ocular neovascularization. The sequence of events by which BMCs participate in ocular neovascularization can be roughly divided into four phases, i.e., mobilization, migration, adhesion and differentiation. This process is delicately regulated and liable to be affected by multiple factors. Cytokines such as vascular endothelial growth factor, granulocyte colony-stimulating factor and erythropoietin are involved in the mobilization of BMCs. Studies have also demonstrated a key role of cytokines such as stromal cell-derived factor-1, tumor necrosis factor-α, as well as vascular endothelial growth factor, in regulating the migration of BMCs. The adhesion of BMCs is mainly regulated by vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and vascular endothelial cadherin. However, the mechanisms regulating the differentiation of BMCs are largely unknown at present. In addition, BMCs secrete cytokines that interact with the microenvironment of ocular neovascularization; their contribution to ocular neovascularization, especially choroidal neovascularization, can be aggravated by several risk factors. An extensive regulatory network is thought to modulate the role of BMCs in the development of ocular neovascularization. A comprehensive understanding of the involved mechanisms will help in the development of novel therapeutic strategies related to BMCs. In this review, we have limited the discussion to the recent progress in this field, especially the research conducted at our laboratory.

Keywords: Bone marrow-derived cells; Mechanism; Ocular neovascularization; Stem cells.

Fig. 1

Pathways and mechanisms underlying the contribution of BMCs in the pathogenesis of ocular neovascularization. BMCs contribute to the development of ocular neovascularization in four phases (mobilization, migration, adhesion and differentiation), and this process is finely regulated by complex signaling pathways. Cytokines, such as VEGF and SDF-1, are involved in mobilization and migration; the adhesion of BMCs is mainly regulated by adhesion molecules including VCAM-1 and ICAM-1. However, the mechanisms regulating the differentiation of BMCs are largely unknown at present. BMCs bone marrow-derived cells, VEGF vascular endothelial growth factor, VEGFR VEGF receptor, G-CSF granulocyte colony-stimulating factor, EPO erythropoietin, HIF-1 hypoxia-inducible factor-1, SDF-1 stromal cell-derived factor-1, CXCR4 CXC receptor-4, eNOS endothelial nitric oxide synthase, MMPs matrix metalloproteinases, MkitL membrane-bound kit ligand, SkitL soluble kit ligand, EC endothelial cells, VSMCs vascular smooth muscle cells, Mφ macrophages, Ang II angiotensin II, ICAM-1 intercellular adhesion molecule-1, VCAM-1 vascular cell adhesion molecule-1

Fig. 2

Role of miR-188-5p in regulating the involvement of BMCs in the pathogenesis of choroidal neovascularization. We observed the relationship between miR-188-5p and MMP-2/13 in MSCs and demonstrated that overexpression of miR-188-5p attenuated the development of CNV as well as the effect of BMCs (unpublished data). These findings are consistent with the hypothesis that miR-188-5p may affect the proliferation, migration and apoptosis of vascular cells and fibrosis of CNV via regulating the MMP-2 and -13 expressions in BMCs, especially MSCs. BMCs bone marrow-derived cells, MSCs mesenchymal stem cells, MMP2/13 matrix metalloproteinase-2/13, VEC vascular endothelial cells