The small and large intestine contain related mesenchymal subsets that derive from embryonic Gli1+ precursors

The intestinal lamina propria contains a diverse network of fibroblasts that provide key support functions to cells within their local environment. Despite this, our understanding of the diversity, location and ontogeny of fibroblasts within and along the length of the intestine remains incomplete. Here we show that the small and large intestinal lamina propria contain similar fibroblast subsets that locate in specific anatomical niches. Nevertheless, we find that the transcriptional profile of similar fibroblast subsets differs markedly between the small intestine and colon suggesting region specific functions. We perform in vivo transplantation and lineage-tracing experiments to demonstrate that adult intestinal fibroblast subsets, smooth muscle cells and pericytes derive from Gli1-expressing precursors present in embryonic day 12.5 intestine. Trajectory analysis of single cell RNA-seq datasets of E12.5 and adult mesenchymal cells suggest that adult smooth muscle cells and fibroblasts derive from distinct embryonic intermediates and that adult fibroblast subsets develop in a linear trajectory from CD81+ fibroblasts. Finally, we provide evidence that colonic subepithelial PDGFRαhi fibroblasts comprise several functionally distinct populations that originate from an Fgfr2-expressing fibroblast intermediate. Our results provide insights into intestinal stromal cell diversity, location, function, and ontogeny, with implications for intestinal development and homeostasis

Repurposing Hydrocarbon Wells for Geothermally-heated Horticulture in the UK

No abstract available

A comprehensive review of deep borehole heat exchangers (DBHEs): subsurface modelling studies and applications

Deep borehole heat exchangers (DBHEs) with depths exceeding 500 m have been researched comprehensively in the literature, focusing on both applications and subsurface modelling. This review focuses on conventional (vertical) DBHEs and provides a critical literature survey to analyse (i) methodologies for modelling; (ii) results from heat extraction modelling; (iii) results from modelling deep borehole thermal energy storage; (iv) results from heating and cooling models; and (v) real case studies. Numerical models generally compare well to analytical models whilst maintaining more flexibility, but often with increased computational resources. Whilst in-situ geological parameters cannot be readily modified without resorting to well stimulation techniques (e.g. hydraulic or chemical stimulation), engineering system parameters (such as mass flow rate of the heat transfer fluid) can be optimised to increase thermal yield and overall system performance, and minimise pressure drops. In this active research area, gaps remain, such as limited detailed studies into the effects of geological heterogeneity on heat extraction. Other less studied areas include: DBHE arrays, boundary conditions and modes of operation. A small number of studies have been conducted to investigate the potential for deep borehole thermal energy storage (BTES) and an overview of storage efficiency metrics is provided herein to bring consistency to the reporting of thermal energy storage performance of such systems. The modifications required to accommodate cooling loads are also presented. Finally, the active field of DBHE research is generating a growing number of case studies, particularly in areas with low-cost drilling supply chains or abandoned hydrocarbon or geothermal wells suitable for repurposing. Existing and planned projects are thus presented for conventional (vertical) DBHEs. Despite growing interest in this area of research, further work is needed to explore DBHE systems for cooling and thermal energy storage

P83 Understanding Differences in Serum and Mucosal Immunopathotypes in Crohn’s Disease

Introduction: Crohn’s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract, characterised by an aberrant immune response towards commensal microbiota. Despite the availability of target-specific front-line therapeutics, 30–40% of CD patients still require surgery to manage disease. This project aims to identify different systemic and mucosal CD immunopathotypes and map their associations to distinct treatment responses and behaviours. Methods: To study local immune response in CD, colonic mucosal biopsies of inflamed patients (CD, n=4) and non-IBD controls (NC, n=6) were analysed by bulk RNA sequencing. Raw counts were normalised using DESeq and further analysed in R studio with a specific pipeline to select differentially expressed genes associated with the immune system. All findings were validated in a selection of three cohorts comparing gene expression of colonic inflamed CD tissue with non-IBD controls (nCD=36, nNC=24). Differences in the systemic immune response were studied in two separate cohorts by isolating plasma and peripheral mononuclear cells (PBMCs) from fresh whole blood of CD patients with different levels of disease activity (n=30) and NCs (n=42). Subsequently, cytokine levels and leukocyte frequencies were measured using multiplex assays and flow cytometry analysis. Results: Gene expression analysis of colonic mucosal tissue biopsies highlighted an immunophenotype driven by macrophage and neutrophil activation and infiltration. After validating this gene cluster in a selection of cohorts, we find that CD patients with colonic active disease can be stratified into three different groups based on their macrophage activation phenotype. In the peripheral blood, we observed that patients have different levels of systemic disease activation, characterised by their leukocyte and cytokine concentrations, independent of their disease activity. Conclusions: Our analyses of mucosal tissue and peripheral blood have provided evidence of different immunopathotypes, both mucosal and systemic. Ongoing work will involve the correlation of these phenotypes with clinical information, such as treatment response and disease progression, to better understand whether pathotypes predict disease behaviour in CD

TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence

Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury mouse model, a transcriptional signature associated with the induction of paracrine senescence was observed within 24 hours and was followed by one of impaired proliferation. In mouse genetic models of hepatocyte injury and senescence, we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended on macrophage-derived transforming growth factor–β1 (TGFβ1) ligand. In acetaminophen poisoning, inhibition of TGFβ receptor 1 (TGFβR1) improved mouse survival. TGFβR1 inhibition reduced senescence and enhanced liver regeneration even when delivered beyond the therapeutic window for treating acetaminophen poisoning. This mechanism, in which injury-induced senescence impairs liver regeneration, is an attractive therapeutic target for developing treatments for acute liver failure