Am J Transplant. 2021 Oct 29.
Danh T Tran,
Zhenxiao Tu,
Ali Alawieh,
Jennifer Mulligan,
Scott Esckilsen,
Kristen Quinn,
Kamala Sundararaj,
Caroline Wallace,
Ryan Finnegan,
Patterson Allen,
Shikhar Mehrotra,
Carl Atkinson,
Satish N Nadig.
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.