Vascular architecture regulates mesenchymal stromal cell heterogeneity via P53-PDGF signaling in the mouse incisor

Mesenchymal stem cells (MSCs) reside in niches to maintain tissue homeostasis and contribute to repair and regeneration. Although the physiological functions of blood and lymphatic vasculature are well studied, their regulation of MSCs as niche components remains largely unknown. Using adult mouse incisors as a model, we uncover the role of Trp53 in regulating vascular composition through THBS2 to maintain mesenchymal tissue homeostasis. Loss of Trp53 in GLI1+ progeny increases arteries and decreases other vessel types. Platelet-derived growth factors from arteries deposit in the MSC region and interact with PDGFRA and PDGFRB. Significantly, PDGFRA+ and PDGFRB+ cells differentially contribute to defined cell lineages in the adult mouse incisor. Collectively, our results highlight Trp53’s importance in regulating the vascular niche for MSCs. They also shed light on how different arterial cells provide unique cues to regulate MSC subpopulations and maintain their heterogeneity. Furthermore, they provide mechanistic insight into MSC-vasculature crosstalk. [Display omitted] •Vascular architecture and its signaling regulate MSC heterogeneity in tissue homeostasis•Loss of Trp53 leads to increased arteries/PDGF signaling and MSC defects in the mouse incisor•Different arterial cells provide unique PDGF signaling to regulate subpopulations of MSCs•PDGFRA+/PDGFRB+ cells differentially contribute to defined cell lineages in the mouse incisor Guo et al. elucidate the role of the vasculature as a niche for mesenchymal stem/stromal cells (MSCs), revealing that P53-PDGF signaling regulates the relative prevalence of arteries and other vessel types. In turn, signaling molecules from the vasculature differentially target MSC subpopulations, contributing to their heterogeneity while maintaining tissue homeostasis.