Biology subjects

Cosme, C.

Publications and source records attributed to Cosme, C..

5 recordsLinked to original sources

bioRxiv2026

Sobetirome, a thyroid hormone receptor beta agonist, is a potential therapeutic agent for pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with limited treatment options. Our group previously identified the antifibrotic potential of thyroid hormone, triiodothyronine (T3); however, clinical translation of thyroid hormone therapy is limited by its systemic adverse effects. In this study, we investigate whether sobetirome, a selective and well tolerated thyroid hormone receptor beta (THRB) agonist, offers antifibrotic benefits of thyroid hormone while minimizing systemic toxicity. Our study reveals that sobetirome, administered via intraperitoneal or inhalational routes, effectively mitigates bleomycin-induced pulmonary fibrosis in mice, with no evidence of toxicity. We identified that sobetirome restores mitochondrial homeostasis via activating the THRB-PPARGC1a axis. This protects alveolar type II epithelial cells from injury-induced apoptosis while selectively inducing apoptosis and metabolic reprogramming in apoptosis resistant IPF fibroblasts. Cell-specific deletion of Ppargc1a in either alveolar epithelial cells or fibroblasts abolishes sobetirome-mediated protection, establishing PPARGC1a as an essential mediator of therapeutic response. Importantly, sobetirome reverses fibrosis-associated transcriptional programs in human IPF lung tissue, reducing expression of key fibrosis-associated genes, including collagen I alpha 1 (COL1A1), collagen III alpha 1 (COL3A1), periostin (POSTN), cathepsin K (CTSK), and Chitinase 3 Like 1 (CHI3L1), while promoting extracellular matrix remodeling, epithelial restoration, and tissue homeostasis. Collectively, our findings identify THRB activation as a novel metabolic strategy for reversing pulmonary fibrosis. Across complementary in vitro, in vivo, and human ex vivo models, sobetirome restores mitochondrial function, modulates apoptotic pathways in pathogenic cells, and promotes fibrosis resolution, highlighting its potential as a lung-targeted therapeutic approach for IPF and other fibrotic lung diseases.

systems biology↗

bioRxiv2022

A dual role for CRTH2 in acute lung injury

Acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition defined by rapid-onset respiratory failure following acute lung injury (ALI). The high mortality rate and rising incidence of ARDS due to COVID-19 make it an important research priority. Here we sought to investigate the role of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) in ARDS. CRTH2 is a G protein-coupled receptor best studied in the context of type 2 immunity, but it also exerts effects on neutrophilic inflammation. To evaluate its role in mouse models of ARDS, we first examined its expression pattern on murine neutrophils. We found it is expressed on neutrophils, but only after extravasation into the lung. Next, we showed that CRTH2 expression on extravasated lung neutrophils promotes cell survival, as genetic deletion of CRTH2 and pharmacologic inhibition of CRTH2 using fevipiprant both led to increased apoptosis in vitro. We then evaluated the role of CRTH2 in vivo using a murine model of LPS-induced ALI. In line with the pro-inflammatory effects of CRTH2 in vitro, we observed improvement of lung injury in CRTH2-deficient mice in terms of vascular leak, weight loss and survival after LPS administration. However, neutrophilic inflammation was elevated, not suppressed in the CRTH2 KO. This finding indicated a second mechanism offsetting the pro-survival effect of CRTH2 on neutrophils. Bulk RNAseq of lung tissue indicated impairments in type 2 immune signaling in the CRTH2 KO, and qPCR and ELISA confirmed downregulation of IL-4, which is known to suppress neutrophilic inflammation. Thus, CRTH2 may play a dual role in ALI, directly promoting neutrophil cell survival, but indirectly suppressing neutrophil effector function via IL-4.

immunology↗

bioRxiv2021

CINS: Cell Interaction Network inference from Single cell expression data

Studies comparing single cell RNA-Seq (scRNA-Seq) data between conditions mainly focus on differences in the proportion of cell types or on differentially expressed genes. In many cases these differences are driven by changes in cell interactions which are challenging to infer without spatial information. To determine cell-cell interactions that differ between conditions we developed the Cell Interaction Network Inference (CINS) pipeline. CINS combines Bayesian network analysis with regression-based modeling to identify differential cell type interactions and the proteins that underlie them. We tested CINS on a disease case control and on an aging human dataset. In both cases CINS correctly identifies cell type interactions and the ligands involved in these interactions. We performed additional mouse aging scRNA-Seq experiments which further support the interactions identified by CINS.

bioinformatics↗

bioRxiv2021

Single Cell RNA-seq and Mass Cytometry Reveals a Novel and a Targetable Population of Macrophages in Idiopathic Pulmonary Fibrosis

In this study, we leveraged a combination of single cell RNAseq, cytometry by time of flight (CyTOF), and flow cytometry to study the biology of a unique macrophage population in pulmonary fibrosis. Using the profiling data from 312,928 cells derived from 32 idiopathic pulmonary fibrosis (IPF), 29 healthy control and 18 chronic obstructive pulmonary disease (COPD) lungs, we identified an expanded population of macrophages in IPF that have a unique transcriptional profile associated with pro-fibrotic signature. These macrophages attain a hybrid transitional state between alveolar and interstitial macrophages, are enriched with biological processes of pro-fibrotic immune cells, and express novel surface markers and genes that have not been previously reported. We then applied single cell CyTOF to simultaneously measure 37 markers to precisely phenotype the uniquely expanded macrophage subset in IPF lungs. The SPADE algorithm independently identified an expanded macrophage cluster, and validated CD84 and CD36 as novel surface markers that highly label this cluster. Using a separate validation cohort, we confirmed an increase in CD84++CD36++ macrophage population in IPF compared to control and COPD lungs by flow cytometry. Further, using the signature from the IPF-specific macrophages and the LINCS drug database, we predicted small molecules that could reverse the signature of IPF-specific macrophages, and validated two molecules, CRT and Cucur, using THP-1 derived human macrophages and precision-cut lung slices (PCLS) from IPF patients. Utilizing a multi-dimensional translational approach, our work identified a novel and targetable population of macrophages found in end-stage pulmonary fibrosis. One Sentence SummarySingle cell RNAseq, CyTOF, and flow cytometry reveal the presence of an aberrant macrophage population in pulmonary fibrosis

cell biology↗

bioRxiv2020

Integrated Single Cell Atlas of Endothelial Cells of the Human Lung

BackgroundDespite its importance in health and disease, the cellular diversity of the lung endothelium has not been systematically characterized in humans. Here we provide a reference atlas of human lung endothelial cells (ECs), to facilitate a better understanding of the phenotypic diversity and composition of cells comprising the lung endothelium, both in health and disease. MethodsWe reprocessed control single cell RNA sequencing (scRNAseq) data from five datasets of whole lungs that were used for the analysis of pan-endothelial markers, we later included a sixth dataset of sorted control EC for the vascular subpopulation analysis. EC populations were characterized through iterative clustering with subsequent differential expression analysis. Marker genes were validated by immunohistochemistry and in situ hybridization. Signaling network between different lung cell types was studied using connectomic analysis. For cross species analysis we applied the same methods to scRNAseq data obtained from mouse lungs. ResultsThe six lung scRNAseq datasets were reanalyzed and annotated to identify over 15,000 vascular EC cells from 73 individuals. Differential expression analysis of EC revealed signatures corresponding to endothelial lineage, including pan-endothelial, pan-vascular and subpopulation-specific marker gene sets. Beyond the broad cellular categories of lymphatic, capillary, arterial and venous ECs we found previously indistinguishable subpopulations; among venous EC we identified two previously indistinguishable populations, pulmonary-venous ECs (COL15A1neg) localized to the lung parenchyma and systemic-venous ECs (COL15A1pos) localized to the airways and the visceral pleura; among capillary EC we confirmed their subclassification into recently discovered aerocytes characterized by EDNRB, SOSTDC1 and TBX2 and general capillary EC. We confirmed that all six endothelial cell types, including the systemic-venous EC and aerocytes are present in mice and identified endothelial marker genes conserved in humans and mice. Ligand-Receptor connectome analysis revealed important homeostatic crosstalk of EC with other lung resident cell types. Our manuscript is accompanied by an online data mining tool (www.LungEndothelialCellAtlas.com). ConclusionOur integrated analysis provides the comprehensive and well-crafted reference atlas of lung endothelial cells in the normal lung and confirms and describes in detail previously unrecognized endothelial populations across a large number of humans and mice.

cell biology↗