Alk1 acts in non-endothelial VE-cadherin+ perineurial cells to maintain nerve branching during hair homeostasis

Vascular endothelial (VE)-cadherin is a well-recognized endothelial cell marker. One of its interacting partners, the TGF-beta receptor Alk1, is essential in endothelial cells for adult skin vasculature remodeling during hair homeostasis. Using single-cell transcriptomics, lineage tracing and gene targeting in mice, we characterize the cellular andmolecular dynamics of skin VE-cadherin(+) cells during hair homeostasis. We describe dynamic changes of VE-cadherin(+) endothelial cells specific to blood and lymphatic vessels and uncover an atypical VE-cadherin(+) cell population. The latter is not a predicted adult endovascular progenitor, but rather a non-endothelialmesenchymal perineurial cell type, which forms nerve encapsulating tubular structures that undergo remodeling during hair homeostasis. Alk1 acts in the VE-cadherin(+) perineurial cells to maintain proper homeostatic nerve branching by enforcing basement membrane and extracellular matrix molecular signatures. Our work implicates the VE-cadherin/Alk1 duo, classically known as endothelial-vascular specific, in perineurial-nerve homeostasis. This has broad implications in vascular and nerve disease.

Automated summary

This study characterizes the cellular and molecular dynamics of skin VE-cadherin(+) cells using single-cell transcriptomics and gene targeting, revealing their specificity in blood and lymphatic vessels and uncovering their role in nerve homeostasis.