Biology subjects

McLinden, A. P.

Publications and source records attributed to McLinden, A. P..

2 recordsLinked to original sources

bioRxiv2025

Characterization of bronchovascular-bundle mesenchymal stromal cells regulating antibody-secreting cell niche in rejecting lung allografts

A transplanted lung offers a permissive milieu for local adaptive immune cell responses. Here, we characterize a transcriptionally and anatomically distinct adult lung-resident mesenchymal stromal population (MSC) that supports a pro-survival niche for antibody-secreting cells in rejecting lung allografts through a novel IL-6 trans-signaling/CXCL12 axis. By using a mouse orthotopic lung transplant model and Blimp1EYFP recipients, we identify spatial localization of antibody-secreting cells (ASCs) and terminally differentiated plasma cells (PCs) along the bronchovascular bundles (BVBs). A previously described Foxf1+Gli1+Itga8- subset of collagen- expressing MSCs, which forms a 3-dimensional network along the bronchovascular bundles (BVB-MSCs), was found to be the major source of the PC survival factors CXCL12 and IL-6. Cxcl12iCre/ERT2Rosa26tdTomatomice utilized as donors, validated the expansion of this population in a rejecting graft and their intimate association with ASCs. CXCL12 expression was increased in murine allografts and in Foxf1+ mesenchymal cells (MCs) isolated from human CLAD patients. IL-6 trans-signaling/STAT3 signaling axis was shown to upregulate CXCL12 secretion in human MCs, and Olamkicept-mediated neutralization of IL-6 trans-signaling in murine RAS attenuates CXCL12 expression, intra-graft ASC population, and fibrogenesis. Our findings represent the first delineation of specialized CXCL12-expressing mesenchymal stromal cells in adult lungs and the contribution of IL-6 trans-signaling driven CXCL12 expression to sustaining intra-graft ASC niches and allograft fibrogenesis. One Sentence SummaryWe characterize CXCL12-expressing mesenchymal cells and their role in a pro-survival niche for antibody-secreting cells in rejecting lung allografts.

pathology↗

bioRxiv2024

Single-cell multi-omic analysis of post-transplant mesenchymal cells reveals molecular signatures and putative regulators of lung fibrosis

Survival after lung transplantation is limited by chronic progressive graft failure, termed chronic lung allograft dysfunction (CLAD). Graft-resident mesenchymal cells (MCs) drive CLAD pathogenesis and exhibit stable, dysregulated signaling; however, the transcriptomic and epigenomic drivers behind this fibrogenic transformation remain elusive. Here, we utilize single-cell multi-omic technologies to study gene expression and chromatin accessibility of MCs from the lavage fluid of lung transplant recipients with and without CLAD, obtained either early post-transplantation or after disease onset. MCs obtained after CLAD onset (CLAD-MCs) demonstrated a unique transcriptomic signature compared to non-CLAD controls; a logistic regression model trained on these profiles classified the disease status of individual cells with > 98% accuracy using a set of signature genes. Chromatin accessibility and motif scan analysis identified the CCAAT-enhancer-binding proteins family of transcription factors, specifically CEBPD, as a key marker of the CLAD-enriched subtype. Footprint analysis of early time-point MCs revealed minimal differences in accessibility, suggesting that CEBPD-associated regulatory changes emerge over time after transplantation. Integration and unsupervised clustering identified 8 distinct cell states, and a compositional shift was noted uniquely in CLAD-MCs. Knocking down CEBPD with siRNA in CLAD-MCs partially reverted the CLAD transcriptomic signature, confirming its importance in the dysregulated molecular state of CLAD-associated MCs. scRNA-seq analysis on human lung CLAD tissue provided in situ validation of key genes and CEBPD expression changes noted in CLAD-MCs. Our results provide deeper insights into the transcriptomic and epigenomic changes in post-transplant MCs, nominating biomarkers and disease-associated factors with implications for future therapeutic efforts.

bioinformatics↗