MicroRNA-19b-3p dysfunction of mesenchymal stem cell-derived exosomes from patients with abdominal aortic aneurysm impairs therapeutic efficacy

被引：16

作者：

Zhang, Yuxiao ^{[1
,2
]}

Huang, Xiaoran ^{[2
]}

Sun, Tucheng ^{[2
]}

Shi, Linli ^{[2
]}

Liu, Baojuan ^{[2
]}

Hong, Yimei ^{[2
]}

Fu, Qing-Ling ^{[3
]}

Zhang, Yuelin ^{[2
]}

Li, Xin ^{[1
,2
]}

机构：

[1] South China Univ Technol, Sch Med, Guangzhou, Peoples R China

[2] Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Dept Emergency Med, Guangzhou, Guangdong, Peoples R China

[3] Sun Yat Sen Univ, Otorhinolaryngol Hosp, Affiliated Hosp 1, Guangzhou, Peoples R China

来源：

JOURNAL OF NANOBIOTECHNOLOGY | 2023年 / 21卷 / 01期

关键词：

Mesenchymal stem cells; Exosomes; Abdominal aortic aneurysm; Vascular smooth muscle cells; Senescence; EXTRACELLULAR VESICLES; SENESCENCE;

D O I：

10.1186/s12951-023-01894-3

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Senescence of vascular smooth muscle cells (VSMCs) contributes to the formation of abdominal aortic aneurysm (AAA). Although mesenchymal stem cell exosomes (MSC-EXO) have been confirmed to restrict the development of AAA, their biological activity depends largely on the physiological state of the MSCs. This study aimed to compare the effects of adipose-derived MSC-EXO from healthy donors (HMEXO) and AAA patients (AMEXO) on senescence of VSMCs in AAA and explore the underlying mechanisms. An ApoE-/- mouse model of AAA was used to investigate the therapeutic effects of HMEXO, AMEXO or miR-19b-3p-AMEXO on AAA development. This in vitro model of AAA was established by treating VSMCs with Ang II (Angiotensin II). The senescence of VSMCs was determined by senescence-associated beta-galactosidase (SA-beta-gal) staining. The morphology of mitochondria in VSMCs was examined by MitoTracker staining. HMEXO exhibited superior capacity compared with AMEXO to inhibit VSMC senescence and attenuate AAA formation in Ang II-treated ApoE-/- mice. In vitro, both AMEXO and HMEXO inhibited Ang II-induced VSMC senescence via downregulation of mitochondrial fission. Notably, compared with HMEXO, the ability of AMEXO to inhibit VSMC senescence was significantly decreased. miRNA sequencing and the expression of miR-19b-3p was significantly decreased in AMEXO compared with HMEXO. Luciferase assay suggested that MST4 (Mammalian sterile-20-like kinase 4) is a potential target of miR-19b-3p. Mechanistically, miR-19b-3p in HMEXO ameliorated VSMC senescence by inhibiting mitochondrial fission via regulation of the MST4/ERK/Drp1 signaling pathway. Overexpression of miR-19b-3p in AMEXO improved their beneficial effect on AAA formation. Our study reveals that MSC-exosomal miR-19b-3p exerts protective effects against Ang II-induced AAA and VSMC senescence via regulation of the MST4/ERK/Drp1 pathway. The pathological state of AAA patients alters the miRNA components of AMEXO and impairs their therapeutic benefits.

引用

页数：20