Los aloinjertos de pulmón humano experimentan un cambio fibrogénico persistente después del rechazo celular agudo

Acute cellular rejection (ACR) remains a significant challenge in lung transplantation, with incomplete understanding of its molecular mechanisms and pathways linking ACR to chronic lung allograft dysfunction (CLAD).

To characterize the cellular and molecular mechanisms underlying ACR in lung allografts using single cell genomics and identify potential therapeutic targets for CLAD.

Single cell RNA-sequencing of freshly collected lung tissue was performed across 8 pediatric and adult patients with ACR, Resolved ACR, and surveillance biopsies without ACR. Validation included gene microarray analysis, immunofluorescence, and single cell ATAC-seq.

Gene set enrichment analysis revealed persistent TGF-β signaling and PI3K/AKT/mTOR pathway activation in both ACR and Resolved samples, validated by immunofluorescence showing sustained elevation of mTOR activation marker phosphorylated-S6 ribosomal protein and COL3A1. Fibrogenic cells exhibited myofibroblast gene signatures via mesenchymal state transitions rather than epithelial- or endothelial-to-mesenchymal transition. Cell communication analysis showed increased Type II Interferon signaling, with Jak/Stat pathway activation in endothelial and basal cells, and reduced VE-Cadherin staining in ACR. Compositional analysis revealed increased cytotoxic, memory T cells and dendritic cells, with persistent reduction of natural killer cells in ACR and Resolved. Donor/recipient analysis revealed predominantly recipient-derived immune cells in ACR.

Persistent TGF-β and mTOR pathway activation following histologic ACR resolution provides molecular insight into ACR-CLAD linkage and suggests mTOR inhibition and TGF-β blockade as potential therapeutic mechanisms to prevent CLAD.

To review GEO accession GSE274199 (scRNA-seq): Go to https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE274199 Enter token qbojyyaitncvbod into the box Code will be made available upon publication.