Ephrin-B2 acts as a positive regulator of osteogenesis-angiogenesis coupling

The aim of this study was to explore the role and potential mechanisms of Ephrin-B2 signaling in osteogenesis-angiogenesis coupling and to provide guidance for periodontal tissue engineering.

Considering the close relationship between periodontitis and periodontal bone defects, single-cell transcriptomic data from periodontal tissues in published databases (GEO number: GSE171213) were analyzed to characterize Ephrin-B2 signaling between osteoblastic lineages and endothelial cells. To observe the effects and mechanisms of Ephrin-B2 in angiogenesis and periodontal bone regeneration, osteoblasts were constructed that overexpress Ephrin-B2 and were then co-cultured with human umbilical vein cells (HUVECs).

Single-cell sequencing revealed a deficiency in Ephrin-B2 signaling from osteoblastic lineages in periodontitis, resulting in impaired transduction of Ephrin-B2 signaling between osteoblasts and endothelial cells. In an osteoblast-endothelial cell co-culture system, Ephrin-B2 signaling from osteoblasts promoted angiogenesis. The downstream pathway might be related to VEGFR2-PI3K. The cotransplantation of osteoblasts overexpressing Ephrin-B2 and HUVECs facilitated angiogenesis and new bone generation in vivo.

This study confirmed that Ephrin-B2 signaling is an indispensable positive regulatory factor in the osteogenesis-angiogenesis coupling of periodontal tissue remodeling. These findings may help to optimize transplantation strategies and provide a new solution for the targeted treatment of periodontal bone defects.

Sufficient vascularization is a prerequisite for periodontal bone regeneration. The cotransplantation of angiogenic endothelial cells and bone-forming cells is a promising tissue engineering strategy. To facilitate the effect of the transplantation, we found evidence of Ephrin-B2 signaling deficiency in osteoblastic lineages and vascular endothelial cells of periodontitis patients from single-cell sequencing data. Moreover, by constructing a cotransplantation system with overexpression of Ephrin-B2, we found its positive role in promoting periodontal vascularized bone regeneration. The present study elucidates the positive role and potential mechanisms of Ephrin-B2 signaling in osteogenesis-angiogenesis coupling, which will help to promote the effect of periodontal tissue engineering.