The calcium binding protein S100β marks Hedgehog-responsive perivascular stem cells that contribute to intimal thickening following iatrogenic flow restriction

Di Luca, M.; Fitzpatrick, E.; Burtenshaw, D.; Liu, W.; Helt, J.-C.; Hakimjavadi, R.; Corcoran, E.; Gusti, Y.; Sheridan, D.; Harman, S.; Lally, C.; Redmond, E. M.; Cahill, P. A.

doi:10.1101/2020.05.20.105981

bioRxiv · 10.1101/2020.05.20.105981

The calcium binding protein S100β marks Hedgehog-responsive perivascular stem cells that contribute to intimal thickening following iatrogenic flow restriction

Di Luca, M.·Fitzpatrick, E.·Burtenshaw, D.·Liu, W.·Helt, J.-C.·Hakimjavadi, R.·Corcoran, E.·Gusti, Y.·Sheridan, D.·Harman, S.·Lally, C.·Redmond, E. M.·Cahill, P. A.

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Abstract

A 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 S100{beta} vSCs in vivo, we identified S100{beta}/Sca1 cells derived from a S100{beta} non-SMC parent population within lesions that co-localise with smooth muscle -actin (SMA) cells following iatrogenic flow restriction, an effect attenuated following hedgehog inhibition with the smoothened inhibitor, cyclopamine. In vitro, S100{beta}/Sca1 cells isolated from atheroprone regions of the mouse aorta expressed hedgehog signalling components, acquired the di-methylation of histone 3 lysine 4 (H3K4me2) stable SMC epigenetic mark at the Myh11 locus and underwent myogenic differentiation in response to recombinant sonic hedgehog (SHh). Both S100{beta} and PTCH1 cells were present in human vessels while S100{beta} cells were enriched in arteriosclerotic lesions. Recombinant SHh promoted myogenic differentiation of human induced pluripotent stem cell-derived S100{beta} neuroectoderm progenitors In vitro. We conclude that hedgehog responsive S100{beta} vSCs contribute to lesion formation and support targeting hedgehog signalling to treat subclinical arteriosclerosis.

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Di Luca, M., Fitzpatrick, E., Burtenshaw, D., Liu, W., Helt, J.-C., Hakimjavadi, R., Corcoran, E., Gusti, Y., Sheridan, D., Harman, S., Lally, C., Redmond, E. M., Cahill, P. A.. 2020-05-21. The calcium binding protein S100β marks Hedgehog-responsive perivascular stem cells that contribute to intimal thickening following iatrogenic flow restriction. https://doi.org/10.1101/2020.05.20.105981

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