Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Protect Liver Ischemia/Reperfusion Injury by Reducing CD154 Expression on CD4+ T Cells via CCT2

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 Ca²⁺ 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.