Genomic Regulation and Translational Potential of a Novel Smooth Muscle Cell-Derived Cell Type in Atherosclerosis - Smooth muscle cells (SMCs) play major roles in atherosclerosis, a leading cause of cardiovascular disease
(CVD). SMCs can be beneficial or detrimental in atherosclerosis, depending on their transdifferentiation
trajectories into atheroprotective (e.g., fibroblast-like cell) or atherogenic (e.g., macrophage) cell types. My recent
work, combining an SMC-lineage tracing murine model and single-cell RNA sequencing (scRNA-seq), revealed
a novel SMC-derived cell type, “SEM” cell (termed because of co-expression of stem cell, endothelial cell, and
monocyte markers). SMC-derived SEM-like cells have also been identified by other groups. SEM cells highly
express genes related to proatherogenic functions (e.g., inflammation) and may be the precursors for other SMC-
derived cell types (e.g., fibrochondrocyte, macrophage), through which SEM cells may modulate vulnerability
and stability of atherosclerotic lesions. My proof of principle studies in mouse models showed that activation of
retinoic acid (RA) signaling inhibited SMC to SEM cell transition, reduced atherosclerotic burden, and promoted
fibrous cap stability in atherosclerosis. These findings suggest the following central hypotheses: 1) activation of
RA signaling attenuates SMC to SEM cell transition by directly suppressing expression of key SEM cell marker
genes; 2) activation of RA signaling represses proatherogenic functions (e.g., inflammation) of SEM cells during
disease progression; 3) activation of RA signaling is beneficial in established atherosclerosis and accelerates
disease regression by promoting SEM cell atheroprotective functions and differentiation trajectories while
suppressing atheroprone features of SEM cells. These hypotheses will be addressed through the following aims:
Aim 1 (K99 phase) will determine if RA signaling inhibits the SMC to SEM cell transition via RAR/RXR/EZH2-
mediated repression of SEM cell marker genes; Aim 2 (K99 phase) will determine if RA signaling attenuates
SEM cell inflammation during atherosclerosis progression through LXR-mediated repression of inflammatory
genes; Aim 3 (R00 phase) will apply SMC-lineage tracing and atherosclerosis regression mouse models to
determine if RA signaling drives differentiation trajectories of SEM cells towards atheroprotective rather than
atherogenic cell types in advanced atherosclerosis (Aim 3A) and promotes SEM cell apoptosis and subsequent
resorption via macrophage efferocytosis during disease regression (Aim 3B). The proposed studies will be
accomplished in the setting of a comprehensive career development program designed to provide the candidate
with scientific and leadership skills that facilitate the successful transition to an independent investigator in the
field of atherosclerotic CVD. At the K99 phase, the candidate will continue to obtain expertise in molecular,
cellular, and biochemical techniques as well as SMC-lineage tracing and mechanistic and functional investigation
of RA signaling and SEM cells in atherosclerosis mouse models for progressing, advanced, and regressing
lesions. The expert advisory team will guide the candidate in research training, manuscript and grant proposal
preparation, and ultimately in the transition to an independence career over the course of the award period.
