Huize Pan1, Chenyi Xue1, Benjamin J Auerbach2, Mingyao Li3, Muredach P Reilly1,4, Jiaxin Fan3, Alexander C Bashore1, Jian Cui1, Dina Y Yang1, Sarah B Trignano1, Wen Liu1, Jianting Shi1, Chinyere O Ihuegbu1, Erin C Bush5, Jeremy Worley5, Lukas Vlahos5, Pasquale Laise5, Robert A Solomon6, Edward S Connolly6, Andrea Califano5,7,8,9,10, Peter A Sims5,10, Hanrui Zhang1. 1. Division 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. 2. Graduate Group in Genomics and Computational Biology (B.J.A.), University of Pennsylvania, Philadelphia. 3. Department of Biostatistics, Epidemiology, and Informatics (J.F., M.L.), University of Pennsylvania, Philadelphia. 4. Irving Institute for Clinical and Translational Research, Columbia University, New York (M.P.R.). 5. Department of Systems Biology (E.C.B., J.W., L.V., P.L. A.C., P.A.S.), Columbia University Irving Medical Center, New York. 6. Department of Neurologic Surgery, New York-Presbyterian Hospital/Columbia University Irving Medical Center (R.A.S., E.S.C.). 7. Herbert Irving Comprehensive Cancer Center (A.C.), Columbia University Irving Medical Center, New York. 8. JP Sulzberger Columbia Genome Center (A.C.), Columbia University Irving Medical Center, New York. 9. Department of Biomedical Informatics (A.C.), Columbia University Irving Medical Center, New York. 10. Department of Biochemistry and Molecular Biophysics (A.C., P.A.S.), Columbia University Irving Medical Center, New York.
Abstract
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.
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 humanatherosclerotic 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 humanatherosclerotic 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 humanatherosclerosis. 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.
Authors: Bennett G Childs; Cheng Zhang; Fahad Shuja; Ines Sturmlechner; Shawn Trewartha; Raul Fierro Velasco; Darren Baker; Hu Li; Jan M van Deursen Journal: Nat Aging Date: 2021-08-02
Authors: Wei Feng Ma; Chani J Hodonsky; Adam W Turner; Doris Wong; Yipei Song; Jose Verdezoto Mosquera; Alexandra V Ligay; Lotte Slenders; Christina Gancayco; Huize Pan; Nelson B Barrientos; David Mai; Gabriel F Alencar; Katherine Owsiany; Gary K Owens; Muredach P Reilly; Mingyao Li; Gerard Pasterkamp; Michal Mokry; Sander W van der Laan; Bohdan B Khomtchouk; Clint L Miller Journal: Atherosclerosis Date: 2021-11-26 Impact factor: 5.162