Biology subjects

George, P. M.

Publications and source records attributed to George, P. M..

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↗

bioRxiv2020

Systemic analysis of putative SARS-CoV-2 entry and processing genes in cardiovascular tissues identifies a positive correlation of BSG with age in endothelial cells

COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly spread throughout the world with unprecedented global healthcare and socio-economic consequences. There is now an established secondary syndrome of COVID-19 characterised by thrombosis, vascular dysfunction and hypertension, seen in those most severely affected. Advancing age in adults is the single most significant risk factor for hospitalisation and death with COVID-19. In light of the cardiovascular/thrombotic sequalae associated with severe COVID-19 disease and the overwhelming risk that increased age carries, in this study, our aim was to obtain mechanistic insight by interrogating gene expression profiles in cardiovascular tissues and cells. Our focus was on the two putative receptors for SARS-CoV-2, ACE2 and BSG along with a selected range of genes thought to be involved in virus binding/processing. In this study we have made four important observations: (i)Cardiovascular tissues and/or endothelial cells express the required genes for SARS-CoV-2 infection, (ii) SASR-CoV-2 receptor pathways, ACE2/TMPRSS2 and BSG/PPIB(A) polarise to lung/epithelium and vessel/endothelium respectively, (iii) expression of SARS-CoV-2 host genes are, on the whole, relatively stable with age and (iv) notable exceptions were ACE2 which decreases with age in some tissues and BSG which increases with age in endothelial cells. Our data support the idea that that BSG is the dominate pathway utilised by SARS-CoV-2 in endothelial cells and are the first to demonstrate a positive correlation with age. We suggest BSG expression in the vasculature is a critical driver which explains the heightened risk of severe disease and death observed in those >40 years of age. Since BSG is utilised by other pathogens our findings have implications beyond the current pandemic. Finally, because BSG is functions in a range of cardiovascular diseases and fibrosis, our observations may have relevance to our understanding of the diseases associated with aging.

immunology↗

bioRxiv2017

Copy number variants implicate cardiac function and development pathways in earthquake-induced stress cardiomyopathy

The pathophysiology of stress cardiomyopathy (SCM), also known as takotsubo syndrome, is poorly understood. SCM usually occurs sporadically, often in association with a stressful event, but clusters of cases are reported after major natural disasters. There is some evidence that this is a familial condition. We have examined three possible models for an underlying genetic predisposition to SCM. Our primary study cohort consists of 28 women who suffered SCM as a result of two devastating earthquakes that struck the city of Christchurch, New Zealand, in 2010 and 2011. To seek possible underlying genetic factors we carried out exome analysis, Cardio-MetaboChip genotyping array analysis and array comparative genomic hybridization on these subjects. The most striking finding from these analyses was the observation of a markedly elevated rate of rare, heterogeneous copy number variants (CNV) of uncertain clinical significance (in 12/28 subjects). Several of these CNVs clearly impacted on genes of cardiac relevance including RBFOX1, GPC5, KCNRG, CHODL, and GPBP1L1. There is no physical overlap between the CNVs, and the genes they impact do not fall into a clear pathophysiological pathway. However, the recognition that SCM cases display a high rate of unusual CNV, and that SCM predisposition may therefore be associated with these CNVs, offers a novel perspective and a new approach by which to understand this enigmatic condition.

genetics↗