Heat Shock Strengthens the Protective Potential of MSCs in Liver Injury by Promoting EV Release Through Upregulated Autophagosome Formation
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show powerful potential in the treatment of multiple diseases. However, the low yield of MSC-EVs severely restricts their clinical application. Here, heat shock (HS), a moderate external stimulus, can enhance EVs release of MSCs by upregulating autophagosome formation. Mechanistically, HS elevates TRPV2 expression to induce Ca<sup>2+</sup> influx and then promotes the activity of two succinylases, SUCLG2 and OXCT1, followed by increasing the succinylation of YWHAZ (a 14-3-3 protein) at lysine 11 (K11). Acting as an adaptor protein, YWHAZ's succinylation at K11 inhibits its degradation, reinforcing YWHAZ-ULK1 binding, which upregulates ULK1 S555 phosphorylation to promote autophagosome formation and enhance EV release of MSCs. Additionally, the improved therapeutic efficacy of HS-treated MSCs via EV release has been shown in two liver injury models-hepatic ischemia/reperfusion injury (HIRI) and acetaminophen-induced liver injury. These findings proved that HS, an easily implementable and cost-effective method, can be used to elevate MSC-EV yield in mass production.
Authors
- Yasong Liu (ORCID: https://orcid.org/0000-0002-9919-2051)
- Qí Zhāng (ORCID: https://orcid.org/0000-0001-6300-6491)
- Jinliang Liang (ORCID: https://orcid.org/0000-0002-9386-0645)
- Huizhu Lin
- Jun Zheng (ORCID: https://orcid.org/0000-0002-4283-0403)
- Xijing Yan (ORCID: https://orcid.org/0000-0001-8406-4287)
- Zhongying Hu (ORCID: https://orcid.org/0000-0002-6312-2940)
- Jiebin Zhang (ORCID: https://orcid.org/0000-0002-2650-6822)
- Jia Yao
- Haitian Chen (ORCID: https://orcid.org/0000-0002-0533-6983)
- Xuejiao Li (ORCID: https://orcid.org/0000-0003-4197-4509)
- Yihang Gong (ORCID: https://orcid.org/0000-0002-4790-3413)
- Tingting Wang (ORCID: https://orcid.org/0000-0002-2963-0888)
- Cuiping Li (ORCID: https://orcid.org/0000-0002-8021-8039)
- Xiaofeng Yuan (ORCID: https://orcid.org/0000-0002-7988-9257)
- Rong Li (ORCID: https://orcid.org/0000-0003-4951-577X)
- Jiaqi Xiao (ORCID: https://orcid.org/0000-0002-3253-9591)
- Chenhao Jiang
Institutions
- Sun Yat-sen University (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
Publication Details
- Journal
- Journal of Extracellular Vesicles
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1002/jev2.70084
- Citations
- 3
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- National Natural Science Foundation of China
- Sun Yat-sen University
- China Postdoctoral Science Foundation
- Natural Science Foundation of Guangdong Province
- National Key Research and Development Program of China
- Basic and Applied Basic Research Foundation of Guangdong Province