Bone marrow mesenchymal stem cell exosomes suppress phosphate-induced aortic calcification via SIRT6–HMGB1 deacetylation

Stem Cell Research & Therapy

Shu Rong¹  Man Yang¹  Jieshuang Jia¹  Lijie Gu¹  Weijie Yuan¹  Wenqian Wei¹  Xiaodong Guo² 

[1] Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, No. 100, Haining Rd, Hongkou District, 200080, Shanghai, China;Department of Oncology, Yueyang Hospital of Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, 200437, Shanghai, China;

关键词: Chronic kidney disease;    Vascular calcification;    Bone marrow mesenchymal stem cells;    Exosomes;    SIRT6;    HMGB1;   

DOI  :  10.1186/s13287-021-02307-8

来源: Springer

【 摘 要 】

BackgroundVascular calcification associated with chronic kidney disease (CKD) can increase the risk of mortality. Elevated serum levels of high mobility group box 1 (HMGB1) promotes vascular calcification in CKD via the Wnt/β-catenin pathway. Sirtuin 6 (SIRT6) prevents fibrosis in CKD by blocking the expression of β-catenin target genes through deacetylation. This study aimed to investigate whether the inhibition of vascular calcification by bone marrow mesenchymal stem cell (BMSC)-derived exosomes is related to SIRT6 activity and assess the regulatory relationship between HMGB1 and SIRT6.MethodsCKD characteristics, osteogenic markers, calcium deposition, and the differential expression of HMGB1 and SIRT6 have been measured in a 5/6 nephrectomized mouse CKD model fed a high-phosphate diet to induce aortic calcification. In vitro assays were also performed to validate the in vivo findings.ResultsHigh phosphate promotes the translocation of HMGB1 from the nucleus to the cytosol and induces the expression of Runx2, osteopontin, and Msx2. However, BMSC-derived exosomes were found to alleviate CKD-related fibrosis and the induction of osteogenic genes although less significantly when SIRT6 expression is suppressed. SIRT6 was found to modulate the cytosol translocation of HMGB1 by deacetylation in vascular smooth muscle cells.ConclusionOur results indicate that BMSC-derived exosomes inhibit high phosphate-induced aortic calcification and ameliorate renal function via the SIRT6–HMGB1 deacetylation pathway.

【 授权许可】

CC BY