VEGFR1/CXCR4-positive progenitor cells modulate local inflammation and augment tissue perfusion by a SDF-1-dependent mechanism

Abstract

Recruitment and retention of circulating progenitor cells at the site of injured or ischemic tissues facilitates adult neo-vascularization. We hypothesized that cell therapy could modulate local neo-vascularization through the vascular endothelial growth factor (VEGF)/stromal cellderived factor-1 (SDF-1) axis and by paracrine effects on local endothelial cells. We isolated from rat bone marrow a subset of multipotent adult progenitor cell-derived progenitor cells (MDPC). In vitro, MDPCs secreted multiple cytokines related to inflammation and angiogenesis, including monocyte chemotactic protein-1, SDF-1, basic fibroblast growth factor, and VEGF, and expressed the chemokine receptors CXCR4 and VEGFR1. To investigate in vivo properties, we transplanted MDPCs into the ischemic hind limbs of rats. Elevated levels of the chemokine SDF-1 and colocalization of CD11b + cells marked the initial phase of tissue remodeling after cell transplantation. Prolonged engraftment was observed in the adventitialmedial border region of arterioles of ischemic muscles.However, engrafted cells did not differentiate into endothelial or smooth muscle cells. Limb perfusion normalized 4 weeks after cell injection. Inhibition of SDF-1 reduced the engraftment of transplanted cells and decreased endothelial cell proliferation. These findings suggest a two-stage model whereby transplanted MDPCs modulate wound repair through recruitment of inflammatory cells to ischemic tissue. This is an important potential mechanism for cell transplantation, in addition to the direct modulation of local vascular cells through paracrine mechanisms.

Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells

“…The SDF-1/CXCR4 signaling was found to be regulated in endothelial cells through the Notch ligand DLL4 [56]. Wrag et al [57] demonstrated that transplantation of rat bone marrow-derived progenitor cells, positive for VEGFR1 and CXCR4, in ischemic hind limbs increased capillary density by a SDF-1-dependent manner, but did not differentiate into vascular structures like endothelial cells or SMCs. The latter authors demonstrated recruitment of progenitor cells to the adventitialmedial border zone of the vessels.…”

Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells

“…Signaling between endothelial cells, as well as signaling to bone marrow-residing endothelial progenitor cells and stromal cells, [1][2][3] depends both on intercellular contact and the exchange of secretory proteins. 4,5 Additionally, endothelial cells have been demonstrated to secrete exosomes and capture exosomes from various cell types.…”

Monocyte/macrophages promote vasculogenesis in choroidal neovascularization in mice by stimulating SDF-1 expression in RPE cells

“…A previous experiment also has implied that RPE cells may be the most important source of SDF-1 in human CNV [26]. RPE cells are sensitive to inflammatory agents and monocyte interaction [41].…”

“…To search for the main contributor of SDF-1, immunofluorescence for RPE cells and SDF-1 was performed simultaneously in the sections from mild C57/BL mice on day 3, based on the fact that RPE cells have been considered as the main source of SDF-1 in human CNV [26]. Sections were incubated with primary antibodies against pan-cytokeratin (CK) (1:150, Santa Cruz, CA, USA), SDF-1 (1:150, Santa Cruz, CA, USA), and then TRITC and FITC-conjugated secondary antibodies, and finally counterstained with DAPI, examined under the confocal laser scanning microscope.…”