Biology subjects

Dewan, K.

Publications and source records attributed to Dewan, K..

3 recordsLinked to original sources

bioRxiv2026

Endothelial PTBP1 Deletion in Transplanted Cardiac Tissue Limits Cardiac Allograft Vasculopathy

BackgroundCardiac allograft vasculopathy (CAV) is a leading cause of late graft failure and mortality following heart transplantation, with limited therapeutic options. Endothelial cells (ECs), at the interface between the donor graft and host immune system, play a central role in CAV development. However, the molecular mechanisms driving endothelial dysfunction and vascular remodeling in chronic heart transplant rejection remain poorly understood. MethodsTo characterize endothelial alterations associated with CAV, we isolated nuclei from cardiac tissues of four human donor groups: (1) early post-transplant CAV-negative surveillance biopsies, (2) CAV-negative explanted grafts with acute cellular rejection (ACR), (3) late-stage CAV-positive explanted grafts, and (4) naive non-transplanted control hearts. We applied intranuclear cellular indexing of transcriptomes and epitopes (inCITE-seq) to profile endothelial gene expression together with nuclear protein levels of splice factor polypyrimidine tract-binding protein 1 (PTBP1), a key post-transcriptional regulator of endothelial inflammatory responses. Functional relevance of PTBP1 was assessed using endothelial-specific deletion of Ptbp1 in an F1 hybrid murine model of CAV. ResultsIn human CAV, endothelial cells exhibited increased transforming growth factor-{beta} (TGF-{beta}) signaling and reduced oxidative phosphorylation (OxPhos) transcripts. Nuclear PTBP1 protein levels were markedly elevated in CAV endothelium and were associated with TGF-{beta}-responsive transcriptional programs and correlated with clinical indices of cardiac dysfunction. In murine heart transplants, endothelial-specific deletion of Ptbp1 markedly reduced hallmarks of CAV, including neointimal hyperplasia, fibrosis, and lymphocyte activation. At the molecular level, endothelial Ptbp1 deletion prevented suppression of mitochondrial transcripts and preserved mitochondrial content and integrity under hypoxic stress, attenuating interferon signaling in endothelial cells. ConclusionThese findings identify PTBP1 as a central endothelial regulator linking pro-fibrotic stress to mitochondrial dysfunction and immune activation in chronic cardiac allograft rejection. Targeting endothelial PTBP1 may represent a strategy to limit chronic graft injury while minimizing systemic immunosuppression.

immunology↗

bioRxiv2025

Adult mice with neonatal-like T cell subsets exhibit increased susceptibility to Bordetella pertussis and influenza infection

Infants are significantly more susceptible to respiratory infection, often resulting in increased morbidity and hospitalization, and occasionally death. This susceptibility is partially explained by the developing nature of the thymus in human infants at, and for several months after, birth. However, the contribution of T cells produced in this thymic microenvironment to infant immune responses has received minimal investigation. Here, we utilized a previously described mouse model (Foxn1{Delta}/{Delta}) which exhibits a persistently immature thymus. Through further characterization, we have determined that adult Foxn1{Delta}/{Delta} mice retain some unique T cells observed in neonatal mice including CD8{beta}+ {gamma}{delta} T cells and CD8 T cells displaying a memory-like phenotype. For this reason, we assessed the potential of these neonatal-like T responses to two pathogens which disproportionately affect neonates, Bordetella pertussis (Bp) and influenza. Utilizing these infections, we demonstrate that T cells generated in an incompletely developed thymus fail to control or mount an effective response against Bp. We also observe that Foxn1{Delta}/{Delta} mice control acute influenza infection, a response which does not require IL-17. However, the Foxn1{Delta}/{Delta} mice fail to generate an influenza nucleoprotein (NP) specific CD8+ T cell response which is likely associated with their inability to fully clear the infection. Together, these data suggest that Foxn1{Delta}/{Delta} mice can be utilized to study the generation, function, and persistence of some unique T cells made in a neonatal-like thymus.

immunology↗

bioRxiv2025

Characterization of the cardiac proteome of wild-type transthyretin amyloidosis cardiomyopathy

IntroductionMyocardial accumulation of the protein transthyretin (TTR) can result in amyloid TTR cardiomyopathy (ATTR-CM), a form of restrictive heart disease with limited therapies and still generally poor clinical outcomes. The mechanisms by which TTR fibril accumulation elicits cardiac toxicity at the protein level remain largely unknown. Accordingly, we performed untargeted proteomics of ventricular myocardium from patients with ATTR-CM versus controls. MethodsMyocardial tissue from non-failing (NF) controls (n=7) and ATTR-CM (n=4) were assayed by mass spectrometry. HFrEF, HCM, and HFpEF proteomics were acquired from published databases. ResultsA total of 539/7093 (7.6% of total) proteins were found to be differentially expressed in ATTR-CM, 227/359 (42%) upregulated and 312/539 (58%) downregulated. Gene ontology pathway analysis found that downregulated proteins were enriched for oxidative phosphorylation and mitochondrial protein translation pathways, while upregulated proteins were enriched for enhanced endocytosis and intracellular vesicle mediated transport. The latter is not observed in other forms of heart failure. We further identify a profound downregulation of sarcomere protein content, which is also not seen in other cardiomyopathies. ConclusionThe ATTR-CM myocardial proteome identifies endocytosis and intracellular transport as uniquely upregulated processes, whereas sarcomere protein content is uniquely downregulated. Both maybe potential therapeutic targets.

molecular biology↗