Dataset Information

Vascular progenitor cell senescence in patients with Marfan syndrome.

ABSTRACT: Vascular progenitor cells (VPCs) present in the adventitia of the vessel wall play a critical role in the regulation of vascular repair following injury. This study aimed to assess the function of VPCs isolated from patients with Marfan syndrome (MFS). VPCs were isolated from control and MFS donors and characterized. Compared with control-VPCs, MFS-VPCs exhibited cellular senescence as demonstrated by increased cell size, higher SA-?-gal activity and elevated levels of p53 and p21. RNA sequencing showed that several cellular process-related pathways including cell cycle and cellular senescence were significantly enriched in MFP-VPCs. Notably, the expression level of TGF-?1 was much higher in MFS-VPCs than control-VPCs. Treatment of control-VPCs with TGF-?1 significantly enhanced mitochondrial reactive oxidative species (ROS) and induced cellular senescence whereas inhibition of ROS reversed these effects. MFS-VPCs displayed increased mitochondrial fusion and decreased mitochondrial fission. Treatment of control-VPCs with TGF-?1 increased mitochondrial fusion and reduced mitochondrial fission. Nonetheless, treatment of mitofusin2 (Mfn2)-siRNA inhibited TGF-?1-induced mitochondrial fusion and cellular senescence. Furthermore, TGF-?1-induced mitochondrial fusion was mediated by the AMPK signalling pathway. Our study shows that TGF-?1 induces VPC senescence in patients with MFS by mediating mitochondrial dynamics via the AMPK signalling pathway.

SUBMITTER: He H

PROVIDER: S-EPMC6533473 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Vascular progenitor cell senescence in patients with Marfan syndrome.

He Haiwei H Yu Baoqi B Liu Zipeng Z Ye Gen G You Wei W Hong Yimei Y Lian Qizhou Q Zhang Yuelin Y Li Xin X

Journal of cellular and molecular medicine 20190328 6

Vascular progenitor cells (VPCs) present in the adventitia of the vessel wall play a critical role in the regulation of vascular repair following injury. This study aimed to assess the function of VPCs isolated from patients with Marfan syndrome (MFS). VPCs were isolated from control and MFS donors and characterized. Compared with control-VPCs, MFS-VPCs exhibited cellular senescence as demonstrated by increased cell size, higher SA-β-gal activity and elevated levels of p53 and p21. RNA sequencin ...[more]

PMID: 30920150

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Project description:ObjectiveTo delineate temporal and spatial dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS). Approach and Results: We performed single-cell RNA sequencing to study aortic root/ascending aneurysm tissue from Fbn1C1041G/+ (MFS) mice and healthy controls, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adult Fbn1C1041G/+ mouse aortic aneurysm tissue only. Comparison with atherosclerotic aortic data (ApoE-/- mice) revealed similar patterns of SMC modulation but identified an MFS-specific gene signature, including plasminogen activator inhibitor-1 (Serpine1) and Kruppel-like factor 4 (Klf4). We identified 481 differentially expressed genes between modSMC and SMC subsets; functional annotation highlighted extracellular matrix modulation, collagen synthesis, adhesion, and proliferation. Pseudotime trajectory analysis of Fbn1C1041G/+ SMC/modSMC transcriptomes identified genes activated differentially throughout the course of phenotype modulation. While modSMCs were not present in young Fbn1C1041G/+ mouse aortas despite small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adult Fbn1C1041G/+ descending thoracic aortas. Single-cell RNA sequencing from human MFS aortic root aneurysm tissue confirmed analogous SMC modulation in clinical disease. Enhanced expression of TGF-β (transforming growth factor beta)-responsive genes correlated with SMC modulation in mouse and human data sets.ConclusionsDynamic SMC phenotype modulation promotes extracellular matrix substrate modulation and aortic aneurysm progression in MFS. We characterize the disease-specific signature of modSMCs and provide temporal, transcriptomic context to the current understanding of the role TGF-β plays in MFS aortopathy. Collectively, single-cell RNA sequencing implicates TGF-β signaling and Klf4 overexpression as potential upstream drivers of SMC modulation.

Dataset Information

Vascular progenitor cell senescence in patients with Marfan syndrome.

Publications

Vascular progenitor cell senescence in patients with Marfan syndrome.

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