Contribution of Gli1⁺ Adventitial Stem Cells to Smooth Muscle Cells in Atherosclerosis and Vascular Injury

Adventitial stem cells (ASCs), identified by Gli1 expression, have been proposed as key contributors to the vascular smooth muscle cell (SMC) population during atherosclerosis development. However, their precise role remains a subject of debate. To clarify this, a Gli1-CreER lineage tracing tool to track these cells in an atherosclerosis model is initially used. This fate-mapping studies revealed that Gli1⁺ cells contribute to a small subset of SMCs. To definitively differentiate between the true lineage transformation and potential ectopic labeling by Gli1-CreER in SMCs, a dual recombinase-mediated genetic strategy to label Gli1⁺ ASCs while eliminating ectopic labeling in SMCs is developed. The results from this dual lineage tracing approach demonstrated that Gli1⁺ ASCs do not contribute to the SMC population in atherosclerotic plaques. Instead, Gli1⁺ ASCs differentiate into a significant portion of SMCs after vascular anastomosis injury, suggesting their role is context-dependent. These findings challenge current paradigms and highlight the need to reconsider cellular targets for therapeutic interventions in atherosclerosis.