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

Abstract

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.

Nanotheranostics for the Management of Hepatic Ischemia‐Reperfusion Injury

“…[142] For example, Zheng et al demonstrated the key role of Chaperonin containing TCP1 subunit 2 (CCT2) enriched in extracellular vesicles excreted from umbilical cordderived mesenchymal stem cells in the amelioration of the liver IRI (Figure 9). [143] This CCT2-mediated attenuation of liver IRI might result from the downregulation of CD154 level expressed on CD4 + T cells, one main cause of IRI-related inflammatory environments, via Ca 2+ -calcineurin-nuclear factor of activated T cells 1 (NFAT1) pathway. Anger et al found that mesenchymal stromal cell-derived extracellular vesicles could elevate the levels of Ki67-positive hepatocytes and decrease the expression of inflammation-associated genes in mice bearing with hepatic IRI, suggesting a significant potential to attenuate liver damage and improve organ regeneration after hepatic IRI.…”

“…Reproduced with permission. [143] Copyright 2020, WILEY-VCH.…”

“…E,F) Flow cytometry analysis of CD154 expression on E) intrahepatic CD4 + T cells and F) hematoxylin & eosin staining of liver tissues from hepatic IRI mice after treatment with each group. Reproduced with permission [143]. Copyright 2020, WILEY-VCH.…”

The Immunomodulatory Properties of Mesenchymal Stem Cells Play a Critical Role in Inducing Immune Tolerance after Liver Transplantation

“…And a newly published study from the United States put out a novel antifibrotic approach directly targeting signal transducer and activator of transcription 3 (STAT3), which was an important transcription factor associated with liver fibrosis, and this process was accomplished based on the administration of MSCs-derived exosomes embedded with small interference RNAs and antisense oligonucleotides [107]. As for whether MSC-EVs can improve the prognosis of liver transplantation patients, most of the recent studies focused on the process of ischemia-reperfusion injury (IRI) after surgery [108][109][110]. It was reported that the administration of MSC-EVs ameliorated IRI perhaps by enhancing autophagy [108], increasing cell viability and suppressing nuclear factor kappa B activity in hepatocytes [109], or reducing CD154 expression on CD4 + T cells via chaperonin containing TCP1 subunit 2 (CCT2) [110].…”

“…As for whether MSC-EVs can improve the prognosis of liver transplantation patients, most of the recent studies focused on the process of ischemia-reperfusion injury (IRI) after surgery [108][109][110]. It was reported that the administration of MSC-EVs ameliorated IRI perhaps by enhancing autophagy [108], increasing cell viability and suppressing nuclear factor kappa B activity in hepatocytes [109], or reducing CD154 expression on CD4 + T cells via chaperonin containing TCP1 subunit 2 (CCT2) [110]. Although the exact mechanism of MSC-EVs to improve the prognosis of liver transplantation has yet to be fully seen, MSC-EVs are worth recognizing as an emerging and very promising therapeutic agent, especially in the regulation of immune rejection.…”