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‐β‐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‐β1 was much higher in MFS‐VPCs than control‐VPCs. Treatment of control‐VPCs with TGF‐β1 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‐β1 increased mitochondrial fusion and reduced mitochondrial fission. Nonetheless, treatment of mitofusin2 (Mfn2)‐siRNA inhibited TGF‐β1‐induced mitochondrial fusion and cellular senescence. Furthermore, TGF‐β1‐induced mitochondrial fusion was mediated by the AMPK signalling pathway. Our study shows that TGF‐β1 induces VPC senescence in patients with MFS by mediating mitochondrial dynamics via the AMPK signalling pathway.
Highlights
We found that compared with control‐Vascular progenitor cells (VPCs), the senescence of Marfan syndrome (MFS)‐VPCs was greatly enhanced as determined by SA‐β‐gal staining (Figure S1)
VPCs isolated from patients with MFS exhibited cellular senescence
We found that TGF‐β1, via regulation of mitochondrial dynam‐ ics, induced VPC cellular senescence by elevation of mitochondrial reactive oxidative species (ROS) generation
Summary
Marfan syndrome (MFS) is mainly caused by the fibrillin‐1 (FBN1) gene mutation and is a hereditary disorder of connective tissue with effects on multiple systems including cardiovascular, skel‐ etal and ocular.[1]. The results showed that compared with control donors, the percentage of γH2AX positive cells was greatly increased in VPCs from MFS patients (Figure S2A,B). These findings suggest that VPCs isolated from patients with MFS exhibit cellular senescence. Mito‐Tempo treatment down‐regulated the increase in p53 and p21 induced by TGF‐β1 in control‐VPCs (Figure 5G) These results suggest that TGF‐β1 regulates VPC senescence via ROS generation. Western blotting showed that Mfn2‐siRNA administration lead to an increase in p‐Drp[1] level and a decrease in Mfn[2] level in MFS‐VPCs (Figure S6E) It was not clear whether TGF‐β1 induced ROS generation via regula‐ tion of mitochondrial dynamics.
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