Biology subjects

Lopez-Jimenez, E.

Publications and source records attributed to Lopez-Jimenez, E..

3 recordsLinked to original sources

bioRxiv2024

Multiscale single-cell assessment of the fibrotic niche in idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease characterised by excessive extracellular matrix deposition within the lung. Recent advances in single-cell RNA sequencing have identified distinct fibrotic populations, yet their origins and spatial relationships remain incompletely understood. MethodsUsing spatial transcriptomics and Hyperion imaging mass cytometry we compared the cellular composition in formalin fixed paraffin embedded fibrotic lesions (n=9 patients) with control lung (n=9), and cellular interactions were inferred using CellChat V2 ligand-receptor analysis. Monolayers of airway epithelial cells were used to identify changes in keratin (KRT) expression following cell detachment and cyclical mechanical stretch. ResultsSpatial multiomics profiling of human lung cells confirmed the in situ localisation of previously described IPF-enriched populations, and identified a previously unrecognized KRT5low/KRT17 epithelial population derived from airway basal cells that progressively acquiring molecular features of aberrant basaloid cells, forming a unique fibrotic niche enriched with the Secreted Phosphoprotein 1 (SPP1) positive macrophages. Functional studies demonstrated that epithelial detachment and cyclical mechanical stretch drive KRT5 reduction, providing a mechanism for the emergence of this transitional state. In addition, we also identified distinct immune-stromal niches enriched in lymphocytes and alveolar fibroblasts. ConclusionThese findings delineate distinct fibrotic epithelial niches in IPF and support a model in which epithelial loss induces aberrant basaloid differentiation and fibroblast activation, with subsequent airway traction and epithelial detachment generating a secondary niche enriched in basal-derived KRT5low/KRT17 cells and SPP1 macrophages.

molecular biology↗

bioRxiv2024

Association between mosaic loss of chromosome Y and pulmonary fibrosis susceptibility and severity

Background Pulmonary fibrosis (PF) is a rare lung disease with diverse pathogenesis and multiple interconnected underlying biological mechanisms. Mosaic loss of chromosome Y (mLOY) is one of the most common forms of acquired chromosome abnormality in men, which has been reported to be associated with increased risk of various chronic progressive diseases including fibrotic diseases. However, the exact role of mLOY in the development of PF remains elusive and to be elucidated. MethodsWe adopted three complementary approaches to explore the role of mLOY in the pathogenesis of PF. We used copy number on chromosome Y to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. We performed Mendelian randomisation to examine the causal relationship between mLOY, IPF, and telomere length. ResultsThe genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (P = 0.0032). mLOY is related to age (P = 0.00021) and shorter telomere length (P = 0.0081) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells and appears to be related to presence and severity of fibrosis. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY. ConclusionOur study confirms the existence of mLOY in PF patients and suggests that mLOY is not a major driver of IPF. The combined evidence suggests a triangulation model where telomere shortening leads to both IPF and mLOY.

genomics↗

bioRxiv2019

Pluripotency factors regulate the onset of Hox cluster activation in the early embryo

Pluripotent cells are a transient population present in the early mammalian embryo dependent on transcription factors, such as OCT4 and NANOG, which maintain pluripotency while simultaneously suppressing lineage specification. Interestingly, these factors are not exclusive to uncommitted cells, but are also expressed during early phases of differentiation. However, their role in the transition from pluripotency to lineage specification is largely unknown. Using genetic models for controlled Oct4 or Nanog expression during postimplantation stages, we found that pluripotency factors play a dual role in regulating key lineage specifiers, initially repressing their expression and later being required for their proper activation. We show that the HoxB cluster is coordinately regulated in this way by OCT4 binding sites located at the 3 end of the cluster. Our results show that core pluripotency factors are not limited to maintaining the pre-committed epiblast, but are also necessary for the proper deployment of subsequent developmental programs.

developmental biology↗