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Single-Cell Genomics Reveals a Novel Cell State During Smooth Muscle Cell Phenotypic Switching and Potential
Huize Pan1, Chenyi Xue1, Benjamin J Auerbach2
1Division of Cardiology, Department of Medicine (H.P., C.X., A.C.B., J.C., D.Y.Y., S.B.T., W.L., J.S., C.O.I., H.Z., M.P.R.), Columbia University Irving Medical Center, New York.
Background:
Smooth muscle cells (SMCs) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC dedifferentiation, migration, and transdifferentiation into other cell types. Yet how SMCs contribute to the pathophysiology of atherosclerosis remains elusive.
Methods:
To reveal the trajectories of SMC transdifferentiation during atherosclerosis and to identify molecular targets for disease therapy, we combined SMC fate mapping and single-cell RNA sequencing of both mouse and human atherosclerotic plaques. We also performed cell biology experiments on isolated SMC-derived cells, conducted integrative human genomics, and used pharmacological studies targeting SMC-derived cells both in vivo and in vitro.
Results:
We found that SMCs transitioned to an intermediate cell state during atherosclerosis, which was also found in human atherosclerotic plaques of carotid and coronary arteries. SMC-derived intermediate cells, termed "SEM" cells (stem cell, endothelial cell, monocyte), were multipotent and could differentiate into macrophage-like and fibrochondrocyte-like cells, as well as return toward the SMC phenotype. Retinoic acid (RA) signaling was identified as a regulator of SMC to SEM cell transition, and RA signaling was dysregulated in symptomatic human atherosclerosis. Human genomics revealed enrichment of genome-wide association study signals for coronary artery disease in RA signaling target gene loci and correlation between coronary artery disease risk alleles and repressed expression of these genes. Activation of RA signaling by all-trans RA, an anticancer drug for acute promyelocytic leukemia, blocked SMC transition to SEM cells, reduced atherosclerotic burden, and promoted fibrous cap stability.
Conclusions:
Integration of cell-specific fate mapping, single-cell genomics, and human genetics adds novel insights into the complexity of SMC biology and reveals regulatory pathways for therapeutic targeting of SMC transitions in atherosclerotic cardiovascular disease.
Insights
Smooth muscle cells (SMCs) transform into intermediate "SEM" cells during atherosclerosis, which can be therapeutically targeted by retinoic acid (RA) signaling to reduce disease progression and improve plaque stability.
Area of Science:
- Cardiovascular Biology
- Cellular and Molecular Medicine
- Atherosclerosis Research
Background:
- Smooth muscle cells (SMCs) undergo phenotypic switching, including dedifferentiation, migration, and transdifferentiation, contributing to atherosclerosis pathogenesis.
- The precise contribution of SMCs to the pathophysiology of atherosclerosis remains incompletely understood.
Purpose of the Study:
- To elucidate the cellular and molecular mechanisms of SMC transdifferentiation in atherosclerosis.
- To identify novel therapeutic targets for atherosclerotic cardiovascular disease by understanding SMC fate trajectories.
Main Methods:
- Combined SMC fate mapping and single-cell RNA sequencing in mouse and human atherosclerotic plaques.
- Conducted cell biology experiments, integrative human genomics, and in vivo/in vitro pharmacological studies.
Main Results:
- Identified an intermediate SMC-derived cell state, termed
- SEM
- cells, present in human atherosclerotic plaques.
- SEM cells are multipotent, differentiating into macrophage-like, fibrochondrocyte-like cells, or reverting to SMCs.
- Retinoic acid (RA) signaling regulates SMC to SEM cell transition; dysregulated RA signaling correlates with symptomatic atherosclerosis and coronary artery disease risk.
- All-trans RA treatment blocked SMC transition, reduced atherosclerotic burden, and enhanced fibrous cap stability.
Conclusions:
- SMC transitions are a key feature of atherosclerosis, generating multipotent SEM cells.
- RA signaling is a critical regulator of SMC plasticity in atherosclerosis and a potential therapeutic target.
- Integrating single-cell genomics and human genetics provides insights into SMC biology and therapeutic strategies for atherosclerotic cardiovascular disease.
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