Journal
ADVANCED SCIENCE
Volume 7, Issue 18, Pages -Publisher
WILEY
DOI: 10.1002/advs.201903746
Keywords
CCT2; CD4+T cells; extracellular vesicles; liver ischemia; reperfusion injury; mesenchymal stem cells
Categories
Funding
- National key research and development program [2017YFA0104304, 2017ZX10203205]
- National Natural Science Foundation of China [81770648, 81770651, 81802402, 81901943, 81900597, 81972286]
- Guangdong Basic and Applied Basic Research Foundation [2015A030312013, 2017A030311034, 2018A030310323]
- Sci-tech Research Development Program of Guangdong province [2017B020209004, 20169013, 2017B030314027, 2017A020215023, 2018A030313705, 2019A1515011698]
- Medical Scientific Research Foundation of Guangdong Province [A2018130]
- Sci-tech Research Development Program of Guangzhou city [2014Y2-00200, 201604020001, 201508020262, 201400000001-3]
- Young Teacher Development Program of Sun Yat-Sen University [17ykpy57, 19ykpy35, 20ykpy41, 20ykpy33]
- China Postdoctoral Science Foundation [2019M653199]
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As a cause of postoperative complications and early hepatic failure after liver transplantation, liver ischemia/reperfusion injury (IRI) still has no effective treatment during clinical administration. Although the therapeutic potential of mesenchymal stem cells (MSCs) for liver IRI has been previously shown, the underlying mechanisms are not completely clear. It is accepted that MSC-derived extracellular vesicles (MSC-EVs) are newly uncovered messengers for intercellular communication. Herein, it is reported that umbilical cord-derived MSCs (UC-MSCs) improve liver IRI in mice through their secreted EVs. It is also visualized that UC-MSC-EVs mainly concentrate in liver after 6 h of reperfusion. Furthermore, UC-MSC-EVs are found to significantly modulate the membranous expression of CD154 of intrahepatic CD4+ T cells, which is an initiation of inflammatory response in liver and can aggravate liver IRI. Mechanistically, protein mass spectrum analysis is performed and it is revealed that Chaperonin containing TCP1 subunit 2 (CCT2) enriches in UC-MSC-EVs, which regulates the calcium channels to affect Ca(2+)influx and suppress CD154 synthesis in CD4+ T cells. In conclusion, these results highlight the therapeutic potential of UC-MSC-EVs in attenuating liver IRI. This finding suggests that CCT2 from UC-MSC-EVs can modulate CD154 expression of intrahepatic CD4+ T cells during liver IRI through the Ca2+-calcineurin-NFAT1 signaling pathway.
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