Gli1⁺ Cells Couple with Type H Vessels and Are Required for Type H Vessel Formation

Mesenchymal stem/stromal cells (MSCs) reside in the perivascular niche and modulate tissue/organ homeostasis; however, little is known about whether and how their localization and function are linked. Particularly, whether specific MSC subsets couple with and regulate specialized vessel subtypes is unclear. Here, we show that Gli1⁺ cells, which are a subpopulation of MSCs couple with and regulate a specialized form of vasculature. The specific capillaries, i.e., CD31^hiEMCN^hi type H vessels, are the preferable vascular subtype which Gli1⁺ cells are adjacent to in bone. Gli1⁺ cells are further identified to be phenotypically coupled with type H endothelium during bone growth and defect healing. Importantly, Gli1⁺ cell ablation inhibits type H vessel formation associated with suppressed bone generation and regeneration. Mechanistically, Gli1⁺ cells initiate angiogenesis through Gli and HIF-1α signaling. These findings suggest a morphological and functional framework of Gli1⁺ cells modulating coupled type H vasculature for tissue homeostasis and regenerative repair.