Human Bone‐Derived Endothelial Cells Mediate Bone Regeneration via Distinct Expression of KIT Ligand

Abstract Effective bone regeneration remains a significant challenge in surgical practice, particularly due to the limitations associated with autologous bone grafting, such as donor site morbidity and limited bone availability. This study investigated the potential of human bone‐derived endothelial cells (b‐ECs) in mediating bone regeneration, especially in conjunction with bone marrow‐derived mesenchymal stem cells (bm‐MSCs). It is demonstrated that b‐ECs retain unique osteoinductive properties post‐isolation, crucial for promoting bone formation in vivo. Utilizing ectopic and orthotopic xenograft models in immunodeficient mice, these findings revealed that the synergistic interaction of b‐ECs and bm‐MSCs induced rapid and substantial bone formation, highlighting the therapeutic potential of b‐ECs in bone repair strategies. The distinct expression of KIT ligand (KITLG) in b‐ECs emerged as a key factor in these processes. KITLG expression by b‐ECs facilitated the recruitment of c‐Kit+/CD34+ hematopoietic progenitor cells to the osteovascular niche, leading to robust osteogenic differentiation of bm‐MSCs, a process regulated by Notch signaling. Moreover, inducing KITLG expression in non‐bone‐derived endothelial cells conferred similar osteoinductive capabilities. These findings not only enhance the understanding of the intricate interplay between vascular and bone tissues but also open avenues for developing innovative cell‐based approaches for bone regeneration therapy.