Mesenchymal stem cells-derived HIF-1α-overexpressed extracellular vesicles ameliorate hypoxia-induced pancreatic ß cell apoptosis and senescence through activating YTHDF1-mediated protective autophagy.
Bioorg Chem
; 129: 106194, 2022 12.
Article
em En
| MEDLINE
| ID: mdl-36244321
ABSTRACT
Pancreatic islet transplantation is an ideal treatment strategy for type 1 diabetes mellitus (T1DM), but hypoxia-induced pancreatic ß cell death after islet transplantation is the huge obstacle that causes failure of this therapy. Thus, it become necessary to improve pancreatic ß cell viability under hypoxic conditions. In the present study, we designed mesenchymal stem cells (MSCs)-derived hypoxia-inducible factor 1α (HIF-1α)-overexpressed extracellular vesicle (EVs) (HIF-1α-EVs) and found that HIF-1α-EVs was effectively to promote cell viability and autophagy, and suppress cell apoptosis and senescence in the hypoxia-treated pancreatic ß cells. In addition, blockage of autophagy by its inhibitor 3-methyladenine (3-MA) abrogated the rescuing effects of HIF-1α-EVs on hypoxia-induced pancreatic ß cell death. Then, the potential underlying mechanisms by which HIF-1α-EVs triggered protective autophagy were uncovered, and we found that HIF-1α-EVs upregulated YTHDF1, resulting in the upregulation of autophagy-associated proteins (ATG5, ATG2A and ATG14), which were abrogated by deleting m6A writer METTL3. Finally, we verified that HIF-1α-EVs rescued cell viability, and reversed hypoxia-induced pancreatic ß cell apoptosis and senescence in a YTHDF1-dependent manner. Collectively, we concluded that MSCs-derived HIF-1α-EVs activated YTHDF1-mediated protective autophagy to promote pancreatic ß cell survival under hypoxic conditions, and HIF-1α-EVs could be used as candidate treatment strategy to increase the success rate of islet transplantation.
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MEDLINE
Assunto principal:
Células Secretoras de Insulina
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Células-Tronco Mesenquimais
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Vesículas Extracelulares
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article