MicroRNA-19b-3p dysfunction of mesenchymal stem cell-derived exosomes from patients with abdominal aortic aneurysm
Yuxiao Zhang1,2, Xiaoran Huang2, Tucheng Sun2
1School of Medicine, South China University of Technology, Guangzhou, China.
Abstract:
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 β-galactosidase (SA-β-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.
Insights
Mesenchymal stem cell exosomes (MSC-EXO) from healthy donors (HMEXO) are more effective than those from AAA patients (AMEXO) at preventing vascular smooth muscle cell senescence and abdominal aortic aneurysm (AAA) formation. This is due to lower miR-19b-3p levels in AMEXO, which impairs their ability to regulate mitochondrial fission via the MST4/ERK/Drp1 pathway.
Area of Science:
- Cardiovascular Biology
- Cellular Senescence
- Exosome Biology
Background:
- Vascular smooth muscle cell (VSMC) senescence is a key factor in abdominal aortic aneurysm (AAA) development.
- Mesenchymal stem cell exosomes (MSC-EXO) show therapeutic potential for AAA, but their efficacy is influenced by the donor's physiological state.
- Comparing exosomes from healthy donors (HMEXO) and AAA patients (AMEXO) is crucial for understanding therapeutic limitations.
Purpose of the Study:
- To compare the effects of HMEXO and AMEXO on VSMC senescence and AAA formation.
- To elucidate the underlying molecular mechanisms, particularly the role of microRNAs and mitochondrial dynamics.
- To investigate the therapeutic potential of modulating exosomal miR-19b-3p content.
Main Methods:
- Utilized an ApoE-/- mouse model and an in vitro Angiotensin II-induced VSMC senescence model.
- Assessed VSMC senescence using senescence-associated β-galactosidase (SA-β-gal) staining.
- Analyzed mitochondrial morphology via MitoTracker staining and identified miRNA profiles using sequencing.
- Investigated target gene interactions using luciferase assays and Western blotting.
Main Results:
- HMEXO demonstrated superior inhibition of VSMC senescence and AAA formation compared to AMEXO.
- Both HMEXO and AMEXO reduced Ang II-induced VSMC senescence by downregulating mitochondrial fission.
- AMEXO exhibited significantly reduced miR-19b-3p levels, a key inhibitor of MST4/ERK/Drp1 signaling, leading to impaired therapeutic efficacy.
- Overexpressing miR-19b-3p in AMEXO restored their beneficial effects on AAA.
Conclusions:
- MSC-exosomal miR-19b-3p protects against Ang II-induced AAA and VSMC senescence by inhibiting mitochondrial fission via the MST4/ERK/Drp1 pathway.
- The miRNA composition of MSC-EXO is altered in AAA patients, diminishing their therapeutic benefits.
- HMEXO represent a more potent therapeutic agent for AAA than AMEXO, highlighting the importance of donor health status.
