Biology subjects

Chichelnitskiy, E.

Publications and source records attributed to Chichelnitskiy, E..

5 recordsLinked to original sources

bioRxiv2026

Single-cell and spatial transcriptomics resolve airway obliteration in bronchiolitis obliterans syndrome

Background: Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation, and its most frequent phenotype is bronchiolitis obliterans syndrome (BOS), a fibrotic small-airway disease. Mechanistic work has focused on the immune compartment, yet intensified immunosuppression does not alter established disease. Aim: To resolve which structural cell states populate the BOS graft and how they are spatially organized during airway obliteration. Methods: We profiled explanted lungs from 33 BOS patients undergoing re-transplantation and 33 controls, combining single-nucleus RNA sequencing (14 BOS, 13 controls) with targeted spatial transcriptomics of 108 regions (27 BOS, 24 controls) and multiplex immunofluorescence validation. Single-nucleus data were integrated with a published restrictive allograft syndrome (RAS) atlas. Results: Across 175,128 nuclei and 1.67 million spatially resolved cells, BOS lungs harbored a profibrotic circuit of Aberrant Basaloid cells and CTHRC1+ fibrotic fibroblasts previously described in fibrotic lung diseases, including RAS. Spatial mapping identified a CXCL14+TNC+ injury-associated basal cell state arising early in the obliterative cascade, identifying basal cells as their major reservoir. CTHRC1+ fibroblasts expanded subepithelially replacing resident peribronchial fibroblasts, alongside a peribronchial vascular shift toward systemic venous endothelium. The circuit extended beyond the airway wall to the alveolar interface, defining two convergent remodeling fronts. Conclusion: BOS engages structural-cell circuits largely shared with RAS and fibrotic lung diseases, but along an airway-centered rather than parenchyma-centered axis. CLAD thus emerges as a spatial rather than cellular spectrum, defined by anatomical distribution more than cell identity. Shared structural programs may therefore be targetable across CLAD phenotypes.

cell biology↗

bioRxiv2023

Donor tissue-resident memory-like T and NK cells generate a transient peripheral chimerism in lung transplant recipients, potentially protective from chronic lung allograft dysfunction

Lung transplantation (LTx) is the only definite treatment option of patients suffering from end- stage lung disease. Long-term outcome is hampered by chronic allograft dysfunction resulting from poorly defined immune mechanisms. In this study of 97 lung recipients, we demonstrate dynamic changes of T, B and NK cell subsets early after lung transplantation with a selective decrease in memory CD4+ and CD8+ T cells accompanied by a relative increase in NK cells. Simultaneously, donor-derived T and NK cells were detected in recipient blood (n=44) immediately after LTx, persisting for three weeks. Donor T and NK cells displayed a CD69+ but CD103-CD49a- CD25- phenotype, which was shared by T and NK cells in lung perfusion solutions. In order to uncover the origin of these donor T and NK cells, the immune compartment of human lung explant tissue, i.e. trachea and parenchyma, was analyzed and it revealed three major subsets: classical circulating CD69-CD103-CD49a- T and NK cells, CD69+CD103+CD49a+ tissue-resident memory (TRM) T and NK cells and CD69+CD103-CD49a- TRM-like T and NK cells. Single-cell RNA sequencing confirmed the presence of TRM-like subsets with unique features, which reflected the phenotypes of donor T and NK cells and created a transient chimerism in recipient blood. Higher frequencies of donor T cells within the first three weeks showed a tendency for protection from chronic lung allograft dysfunction (CLAD) two years after transplantation although the correlation analyses did not reach statistical significance. To the best of our knowledge, we show for the first time that a transient chimerism is established within the first weeks after lung transplantation by donor TRM- like T and NK cells, which may contribute to protection from chronic lung allograft dysfunction (CLAD) development. Single Sentence SummaryDonor TRM-like T and NK cells cause a transient chimerism in lung recipients and potentially contribute to protection from CLAD.

immunology↗

bioRxiv2022

Rnf20 shapes the endothelial control of heart morphogenesis and function

During embryogenesis, distinct cardiac cell types form, which shape the structural and functional properties of the heart. How their activity is coordinated is largely unknown. Here we show that Rnf20 is a multifaceted regulator of cardiac morphogenesis and function. On the one hand, Rnf20 controls extracellular matrix dynamics and endothelial-cardiomyocyte crosstalk essential for second heart field development. On the other hand, it safeguards endothelial cell identity and function by maintaining physiological angiocrine signaling and preventing endothelial-to-mesenchymal transition. Endothelial-specific deletion of Rnf20 led to ventricular septal defects, myocardial thinning and cardiac dysfunction as a result of aberrant signaling and excessive extracellular matrix deposition that induced precocious cardiomyocyte binucleation and irregular contractility. Furthermore, we uncovered upstream factors (e.g. Sox9) and multiple angiocrine and extracellular matrix molecules that alter cardiomyocyte functionality upon endothelial Rnf20 loss. In summary, our work identifies a novel, endothelial-specific role of Rnf20 in regulating cardiac morphogenesis and function.

developmental biology↗

bioRxiv2022

An integrated cell atlas of the human lung in health and disease

Organ- and body-scale cell atlases have the potential to transform our understanding of human biology. To capture the variability present in the population, these atlases must include diverse demographics such as age and ethnicity from both healthy and diseased individuals. The growth in both size and number of single-cell datasets, combined with recent advances in computational techniques, for the first time makes it possible to generate such comprehensive large-scale atlases through integration of multiple datasets. Here, we present the integrated Human Lung Cell Atlas (HLCA) combining 46 datasets of the human respiratory system into a single atlas spanning over 2.2 million cells from 444 individuals across health and disease. The HLCA contains a consensus re-annotation of published and newly generated datasets, resolving under- or misannotation of 59% of cells in the original datasets. The HLCA enables recovery of rare cell types, provides consensus marker genes for each cell type, and uncovers gene modules associated with demographic covariates and anatomical location within the respiratory system. To facilitate the use of the HLCA as a reference for single-cell lung research and allow rapid analysis of new data, we provide an interactive web portal to project datasets onto the HLCA. Finally, we demonstrate the value of the HLCA reference for interpreting disease-associated changes. Thus, the HLCA outlines a roadmap for the development and use of organ-scale cell atlases within the Human Cell Atlas.

cell biology↗

bioRxiv2020

Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, creates an urgent need for identifying molecular mechanisms that mediate viral entry, propagation, and tissue pathology. Cell membrane bound angiotensin-converting enzyme 2 (ACE2) and associated proteases, transmembrane protease serine 2 (TMPRSS2) and Cathepsin L (CTSL), were previously identified as mediators of SARS-CoV2 cellular entry. Here, we assess the cell type-specific RNA expression of ACE2, TMPRSS2, and CTSL through an integrated analysis of 107 single-cell and single-nucleus RNA-Seq studies, including 22 lung and airways datasets (16 unpublished), and 85 datasets from other diverse organs. Joint expression of ACE2 and the accessory proteases identifies specific subsets of respiratory epithelial cells as putative targets of viral infection in the nasal passages, airways, and alveoli. Cells that co-express ACE2 and proteases are also identified in cells from other organs, some of which have been associated with COVID-19 transmission or pathology, including gut enterocytes, corneal epithelial cells, cardiomyocytes, heart pericytes, olfactory sustentacular cells, and renal epithelial cells. Performing the first meta-analyses of scRNA-seq studies, we analyzed 1,176,683 cells from 282 nasal, airway, and lung parenchyma samples from 164 donors spanning fetal, childhood, adult, and elderly age groups, associate increased levels of ACE2, TMPRSS2, and CTSL in specific cell types with increasing age, male gender, and smoking, all of which are epidemiologically linked to COVID-19 susceptibility and outcomes. Notably, there was a particularly low expression of ACE2 in the few young pediatric samples in the analysis. Further analysis reveals a gene expression program shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues, including genes that may mediate viral entry, subtend key immune functions, and mediate epithelial-macrophage cross-talk. Amongst these are IL6, its receptor and co-receptor, IL1R, TNF response pathways, and complement genes. Cell type specificity in the lung and airways and smoking effects were conserved in mice. Our analyses suggest that differences in the cell type-specific expression of mediators of SARS-CoV-2 viral entry may be responsible for aspects of COVID-19 epidemiology and clinical course, and point to putative molecular pathways involved in disease susceptibility and pathogenesis.

bioinformatics↗