i
Modulating Donor Mitochondrial Fusion/Fission Delivers Immunoprotective Effects in Cardiac Transplantation
-
2 2022
Source: Am J Transplant. 22(2):386-401 -
Alternative Title:Am J Transplant
-
Publisher's site:
-
Personal Author:
-
Description:Early insults associated with cardiac transplantation increase the immunogenicity of donor microvascular endothelial cells (ECs), which interact with recipient alloreactive memory T cells and promote responses leading to allograft rejection. Thus, modulating EC immunogenicity could potentially alter T cell responses. Recent studies have shown modulating mitochondrial fusion/fission alters immune cell phenotype. Here, we assess whether modulating mitochondrial fusion/fission reduces EC immunogenicity and alters EC-T cell interactions. By knocking down DRP1, a mitochondrial fission protein, or by using the small molecules M1, a fusion promoter, and Mdivi1, a fission inhibitor, we demonstrate that promoting mitochondrial fusion reduced EC immunogenicity to allogeneic CD8| T cells, shown by decreased T cell cytotoxic proteins, decreased EC VCAM-1, MHC-I expression, and increased PD-L1 expression. Co-cultured T cells also displayed decreased memory frequencies and Ki-67 proliferative index. For in vivo significance, we used a novel murine brain-dead donor transplant model. Balb/c hearts pretreated with M1/Mdivi1 after brain-death induction were heterotopically transplanted into C57BL/6 recipients. We demonstrate that, in line with our in vitro studies, M1/Mdivi1 pretreatment protected cardiac allografts from injury, decreased infiltrating T cell production of cytotoxic proteins, and prolonged allograft survival. Collectively, our data show promoting mitochondrial fusion in donor ECs mitigates recipient T cell responses and leads to significantly improved cardiac transplant survival.
-
Subject:
-
Source:
-
Pubmed ID:34714588
-
Pubmed Central ID:PMC8813895
-
Document Type:
-
Funding:
-
Collection(s):
-
Main Document Checksum:
-
File Type:
-
gif jpeg gif jpeg gif jpeg gif jpeg xml docx gif jpeg gif jpeg gif jpeg gif jpeg
Details:
Supporting Files
More +