Lineage-Driven Understanding of Human Pericyte Heterogeneity in Vascular Modeling and Regeneration

Abstract

Pericytes are mural cells embedded within the microvascular wall that regulate endothelial stabilization, angiogenesis, and vascular permeability. Once regarded as a relatively uniform vascular support population, pericytes are now recognized as quantitatively and functionally heterogeneous across organs. Neural barrier beds such as brain and retina exhibit high pericyte density and near-continuous mural coverage, whereas peripheral tissues including skeletal muscle display sparse investment. These anatomical differences parallel functional specialization, with central nervous system pericytes exerting strong control over blood-brain barrier (BBB) integrity and transcytosis, while peripheral pericytes participate prominently in vascular remodeling and repair. A critical yet under-integrated dimension of this heterogeneity is developmental origin. Trunk and visceral pericytes arise predominantly from mesodermal progenitors, whereas cranial and forebrain-associated pericytes derive largely from neural crest lineage. This spatial segregation of embryonic origin aligns with vascular specialization, suggesting that lineage contributes to mural regulatory architecture. Stem cell-based comparisons further demonstrate that neural crest-derived pericyte-like cells induce BBB phenotypes more effectively than mesoderm-derived counterparts under identical endothelial conditions, supporting a lineage-linked functional bias. This review integrates anatomical distribution, quantitative investment patterns, molecular signaling mechanisms, and embryonic lineage into a unified framework of pericyte heterogeneity. We propose that developmental origin establishes a regulatory foundation upon which vascular niche signals act, and should therefore be treated as a primary experimental and translational design variable in vascular modeling and regenerative strategies.