The Paracrine Role of Endothelial Cells in Bone Formation via CXCR4/SDF-1 Pathway

Abstract

Vascularization is a prerequisite for bone formation. Endothelial progenitor cells (EPCs) stimulate bone formation by creating a vascular network. Moreover, EPCs secrete various bioactive molecules that may regulate bone formation. The aim of this research was to shed light on the pathways of EPCs in bone formation. In a subcutaneous nude mouse ectopic bone model, the transplantation of human EPCs onto β-TCP scaffold increased angiogenesis (p < 0.001) and mineralization (p < 0.01), compared to human neonatal dermal fibroblasts (HNDF group) and a-cellular scaffold transplantation (β-TCP group). Human EPCs were lining blood vessels lumen; however, the majority of the vessels originated from endogenous mouse endothelial cells at a higher level in the EPC group (p < 01). Ectopic mineralization was mostly found in the EPCs group, and can be attributed to the recruitment of endogenous mesenchymal cells ten days after transplantation (p < 0.0001). Stromal derived factor-1 gene was expressed at high levels in EPCs and controlled the migration of mesenchymal and endothelial cells towards EPC conditioned medium in vitro. Blocking SDF-1 receptors on both cells abolished cell migration. In conclusion, EPCs contribute to osteogenesis mainly by the secretion of SDF-1, that stimulates homing of endothelial and mesenchymal cells. This data may be used to accelerate bone formation in the future.

Endothelial Progenitor Cells Induce Osteogenic Differentiation in Co-cultured Mesenchymal Stem Cells via the MAPK Signaling Pathway

“…Such as VEGF and its receptor, which reported to induce the osteogenic differentiation of stem cells, and recruit major bone-forming cells [56,57]. These results were also consistent with the study of Tal et al, which concluded that EPCs can enhance osteogenesis by stimulating proliferation of surrounding cells via a paracrine effect [58].Although further studies are needed, all these results suggested that an important paracrine signaling occurs between EPCs and MSCs by indirect contact.…”

3D-Bioprinting Strategies Based on In Situ Bone-Healing Mechanism for Vascularized Bone Tissue Engineering

“…Bone formation processes include osteogenic differentiation of MSCs, maturation of matrix, and mineralization [ 1 ]. During this process, MSCs proliferate into the areas where neovascularization is highly activated, forming a close physical proximity to blood vessels, and continue to differentiate into osteoblasts contributing to bone matrix synthesis [ 47 ]. Previous studies have reported that blood vessel-forming cells such as ECs and endothelial progenitor cells (EPCs) are pivotal in neo-vascularization in the new bone matrix and also in bone cell development and activity during bone healing [ 47 , 48 , 49 ].…”

“…During this process, MSCs proliferate into the areas where neovascularization is highly activated, forming a close physical proximity to blood vessels, and continue to differentiate into osteoblasts contributing to bone matrix synthesis [ 47 ]. Previous studies have reported that blood vessel-forming cells such as ECs and endothelial progenitor cells (EPCs) are pivotal in neo-vascularization in the new bone matrix and also in bone cell development and activity during bone healing [ 47 , 48 , 49 ]. Therefore, proper coordination to arrange the synergistic cellular crosstalk between MSCs and ECs or EPCs is of utmost importance for vascularized BTE approaches.…”

“…Therefore, proper coordination to arrange the synergistic cellular crosstalk between MSCs and ECs or EPCs is of utmost importance for vascularized BTE approaches. MSCs are versatile in bone regeneration because they proliferate and then differentiate into osteoblasts to act as fundamental components of bone formation, and also support blood vessel formation by stimulating the migration, proliferation, and differentiation of vascular cells while secreting a variety of angiogenic factors such as VEGF, FGF, BMP-2, and IGF [ 47 , 49 ]. Furthermore, they can also differentiate into perivascular cells, thus serving as a main resource of new blood vessels [ 11 , 50 , 51 ].…”

Endothelial progenitor cells promote osteogenic differentiation in co-cultured with mesenchymal stem cells via the MAPK-dependent pathway

“…MSCs endocytosed exosomes via the caveolar will trigger the activation of p38MAPK pathway by phosphorylating mechanism [65]. Researchers also found that EPCs enhance osteogenesis by stimulating proliferation of surrounding cells via a paracrine effect [66]. Such as VEGF and its receptor, which reported to induce the osteogenic differentiation of stem cells, recruit major bone-forming cells, and stimulating the release of BMP-2 by osteoblast [67][68][69].…”