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

## TL;DR

This study shows that Gli1+ stem cells do not become smooth muscle cells in atherosclerosis but do so after vascular injury, changing how we think about cell roles in disease.

## Contribution

The study introduces a dual-recombinase lineage tracing method to clarify the true contribution of Gli1+ ASCs in different vascular contexts.

## Key findings

- Gli1+ ASCs do not contribute to smooth muscle cells in atherosclerotic plaques.
- Gli1+ ASCs differentiate into smooth muscle cells after vascular anastomosis injury.
- The role of Gli1+ ASCs is context-dependent, challenging previous assumptions about their function in atherosclerosis.

## Abstract

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.

Gli1+ adventitial stem cells (ASCs) have been thought to generate smooth muscle cells (SMCs) in atherosclerosis. Using a dual‐recombinase lineage tracing to exclude ectopic labeling, Wang et al. found that Gli1+ ASCs do not contribute to SMCs in atherosclerotic plaques. Instead, Gli1+ ASCs contribute to a substantial portion of SMCs after vascular anastomosis injury, indicating a context‐dependent role. These results challenge existing views and urge a re‐evaluation of therapeutic targets for atherosclerosis.