The calcium binding protein S100β marks Hedgehog-responsive perivascular stem cells that contribute to intimal thickening following iatrogenic flow restriction
SummaryA hallmark of subclinical atherosclerosis is the accumulation of vascular smooth muscle cell (SMC)-like cells leading to intimal thickening. While medial SMCs contribute, the participation of hedgehog responsive resident vascular stem cells (vSCs) to lesion formation remains unclear. Using transgenic eGFP mice and genetic lineage tracing of S100β vSCs in vivo, we identified S100β/Sca1 cells derived from a perivascular S100β non-SMC parent population within lesions following iatrogenic flow restriction, an effect attenuated following hedgehog inhibition with cyclopamine. Multipotent S100β/Sca1 vSCs acquired the stable SMC epigenetic H3K4me2 histone mark at the Myh11 locus and underwent myogenic differentiation in response to sonic hedgehog (SHh) in vitro. S100β cells were enriched in human arteriosclerotic lesions while SHh promoted myogenic differentiation of human induced pluripotent stem cell derived S100β neuroectoderm progenitors in vitro. We conclude that hedgehog responsive S100β vSCs contribute to lesion formation and support targeting hedgehog signalling to treat subclinical arteriosclerosis.