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A rare pre-existing progenitor-like Primed SMC compartment is the dominant inferred source of SMC-derived cellularity in vascular injury and atherosclerosis

Wani, S., Kitching, M., Aboulhassanzadeh, S., Lungu, T.-S., Kilicgun, I., Ulibarri, K., Liu, W., Floudas, A., Redmond, E. M., Cahill, P. A.
10.64898/2026.06.28.735042 · was preprinted
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Abstract

The cellular origin of smooth muscle cell (SMC)-derived populations in vascular lesions remains unresolved. Here we show, using single-cell transcriptomic analyses spanning carotid ligation injury, Myh11-CreERT{superscript 2}-traced aortic homeostasis, and LDLR- and ApoE-deficient atherosclerosis, that a rare progenitor-like "Primed" SMC compartment pre-exists at baseline in all models and in the healthy human aorta. Relative to contractile SMCs, Primed SMCs attenuate sarcomeric and contractile programmes while inducing matricellular, progenitor-niche and chondrogenic-poised developmental programmes, resolving into conserved niche/progenitor (Cd34, Fst, Tnfrsf11b) and matricellular (Vcam1, Thbs1, Timp1) cores overlaid by vessel-specific signatures, on a retained SMC identity. Multiple orthogonal computational lineage-inference approaches indicate that this compartment expands predominantly through autonomous self-renewal and is the dominant inferred source of cycling and lesion fibrochondrocyte populations, while contractile SMCs are consistently depleted as a feeder source. These findings reframe lesional SMC cellularity as expansion of a pre-existing Primed compartment rather than widespread phenotypic switching of contractile SMCs.

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