Single-cell genomics reveals a novel cell state during smooth muscle cell phenotypic switching and potential therapeutic targets for atherosclerosis in mouse and human [human]
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ABSTRACT: Single-cell genomics reveals a novel cell state during smooth muscle cell phenotypic switching and potential therapeutic targets for atherosclerosis in mouse and human [human]
Project description:Smooth muscle cells (SMC) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC dedifferentiation, migration and transdifferentiation into other cell types. Yet, how SMC contribute to pathophysiology of atherosclerosis remains elusive. 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.
Project description:Smooth muscle cells (SMC) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC dedifferentiation, migration and transdifferentiation into other cell types. Yet, how SMC contribute to pathophysiology of atherosclerosis remains elusive. 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.
Project description:Single-cell genomics reveals a novel cell state during smooth muscle cell phenotypic switching and potential therapeutic targets for atherosclerosis in mouse and human
Project description:Single-cell genomics reveals a novel cell state during smooth muscle cell phenotypic switching and potential therapeutic targets for atherosclerosis in mouse and human [mouse]
Project description:Vascular smooth muscle cells (VSMCs) within atherosclerotic lesions undergo a phenotypic switching in a KLF4-dependent manner. Glycolysis plays important roles in transdifferentiation of somatic cells, however, it is unclear whether and how KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions. Here, we show that KLF4 upregulation accompanies VSMCs phenotypic switching in atherosclerotic lesions. KLF4 enhances the metabolic switch to glycolysis through increasing PFKFB3 expression. Inhibiting glycolysis suppresses KLF4-induced VSMCs phenotypic switching, demonstrating that glycolytic shift is required for VSMCs phenotypic switching. Mechanistically, KLF4 upregulates expression of circCTDP1 and eEF1A2, both of which cooperatively promote PFKFB3 expression. TMAO induces glycolytic shift and VSMCs phenotypic switching by upregulating KLF4. Our study indicates that KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions, suggesting that a previously unrecognized KLF4-eEF1A2/circCTDP1-PFKFB3 axis plays crucial roles in VSMCs phenotypic switching.
Project description:Vascular smooth muscle cells (SMCs) normally exist in a contractile state but can undergo fate switching to produce a variety of cell phenotypes in response to pathologic stimuli. In atherosclerosis, these phenotypically modulated SMCs play a critical role in determining plaque composition and the risk of major adverse cardiovascular events. We found that PRDM16, a transcription factor that has been genetically implicated in cardiovascular disease, is highly expressed in arterial SMCs, and downregulated during SMC fate switching in human and mouse atherosclerosis. Deletion of Prdm16 in SMCs of mice activates the synthetic modulation program in arteries under homeostatic conditions. Upon exposure to atherogenic conditions, these mice form strikingly dense, SMC-rich, fibroproliferative plaques that contain few foam cells. Acute deletion of Prdm16 in SMCs triggers a similar fibrotic response, resulting in the formation of collagen-rich lesions with thick fibrous caps – a hallmark of enhanced lesion stability. Reciprocally, ectopic expression of PRDM16 in cultured cells is sufficient to block SMC synthetic processes, including migration, proliferation, and fibrosis. Mechanistically, PRDM16 binds to chromatin and decreases activating histone marks at synthetic genes. Altogether, our results define PRDM16 as a specific gatekeeper of the synthetic SMC switch and reveal that PRDM16 levels in SMCs predetermine atherogenic lesion composition.
Project description:Vascular smooth muscle cells (SMCs) normally exist in a contractile state but can undergo fate switching to produce a variety of cell phenotypes in response to pathologic stimuli. In atherosclerosis, these phenotypically modulated SMCs play a critical role in determining plaque composition and the risk of major adverse cardiovascular events. We found that PRDM16, a transcription factor that has been genetically implicated in cardiovascular disease, is highly expressed in arterial SMCs, and downregulated during SMC fate switching in human and mouse atherosclerosis. Deletion of Prdm16 in SMCs of mice activates the synthetic modulation program in arteries under homeostatic conditions. Upon exposure to atherogenic conditions, these mice form strikingly dense, SMC-rich, fibroproliferative plaques that contain few foam cells. Acute deletion of Prdm16 in SMCs triggers a similar fibrotic response, resulting in the formation of collagen-rich lesions with thick fibrous caps – a hallmark of enhanced lesion stability. Reciprocally, ectopic expression of PRDM16 in cultured cells is sufficient to block SMC synthetic processes, including migration, proliferation, and fibrosis. Mechanistically, PRDM16 binds to chromatin and decreases activating histone marks at synthetic genes. Altogether, our results define PRDM16 as a specific gatekeeper of the synthetic SMC switch and reveal that PRDM16 levels in SMCs predetermine atherogenic lesion composition.
Project description:Human atherosclerotic plaque cells display DNA damage that can promote premature cell senescence. Vascular smooth muscle cells (VSMCs) predisposed to senescence promote atherogenesis and features of unstable plaques, and increase injury-induced neointima formation. However, how premature senescence promotes vascular disease is unknown. Two independent in vitro models of VSMC senescence induced a range of modulated VSMC phenotype markers, whose expression domains overlapped with senescence markers in atherosclerotic plaque scRNA-seq datasets of human and mouse VSMCs. Mice expressing a VSMC-restricted mutant telomere protein (TRF2T188A) increased expression of multiple de-differentiation genes in vivo in atherosclerosis and after injury, and pathways associated with extracellular matrix organisation, inflammation and Tgfb response. Trf2T188A VSMCs had defective Tgfb signaling and were resistant to Tgfb-induced re-differentiation. Our results suggest that VSMC senescence promotes atherosclerosis and neointima formation in part by driving inflammation and inhibiting re-differentiation of VSMCs.
Project description:RNA sequencing of primary human aortic or arterial VSMCs after stimulation with transforming growth factor beta-1 (TGFβ1) revealed marked IL11 upregulation. In vitro, IL11 stimulation of VSMCs resulted in phenotypic switching by increased ECM production and migration/invasion. Neutralizing IL11 antibody treatment abolished phenotypic switching in VSMCs. IL11 plays an important and non-redundant role in VSMC phenotypic switching.
Project description:Vascular smooth muscle cells (SMCs) normally exist in a contractile state but can undergo fate switching to produce a variety of cell phenotypes in response to pathologic stimuli. In atherosclerosis, these phenotypically modulated SMCs play a critical role in determining plaque composition and the risk of major adverse cardiovascular events. We found that PRDM16, a transcription factor that has been genetically implicated in cardiovascular disease, is highly expressed in arterial SMCs, and downregulated during SMC fate switching in human and mouse atherosclerosis. Deletion of Prdm16 in SMCs of mice activates the synthetic modulation program in arteries under homeostatic conditions. Upon exposure to atherogenic conditions, these mice form strikingly dense, SMC-rich, fibroproliferative plaques that contain few foam cells. Acute deletion of Prdm16 in SMCs triggers a similar fibrotic response, resulting in the formation of collagen-rich lesions with thick fibrous caps – a hallmark of enhanced lesion stability. Reciprocally, ectopic expression of PRDM16 in cultured cells is sufficient to block SMC synthetic processes, including migration, proliferation, and fibrosis. Mechanistically, PRDM16 binds to chromatin and decreases activating histone marks at synthetic genes. Altogether, our results define PRDM16 as a specific gatekeeper of the synthetic SMC switch and reveal that PRDM16 levels in SMCs predetermine atherogenic lesion composition.