Biology subjects

Giger, M.

Publications and source records attributed to Giger, M..

3 recordsLinked to original sources

bioRxiv2026

Dysferlin is a novel regulator of COMP-positive matrifibrocytes in heart failure

Background and AimsCardiac fibrosis is a major contributor to heart failure (HF), yet mechanisms limiting pathological fibroblast activation remain incompletely understood. We identified dysferlin (DYSF), a membrane repair protein, as highly induced in HF fibroblasts and investigated its role in regulating profibrotic responses. MethodsCardiac fibroblasts from patients with end-stage HF and unaffected donor hearts were analysed by liquid chromatography-tandem mass spectrometry and bulk RNA sequencing. Dysferlin expression was validated in independent cohorts. Selected gene/protein expression was validated using single-cell/single-nucleus RNA sequencing and multiplex immunofluorescence of human myocardium from dilated cardiomyopathy (DCM), ischaemic cardiomyopathy (ICM), acute myocardial infarction (AMI), and unaffected hearts. Functional studies were performed in human and mouse cardiac fibroblasts using siRNA-mediated silencing and TGF-{beta} stimulation, and in engineered human 3D cardiac microtissues. Fibrotic remodelling, autophagy, apoptosis, and contractile function were assessed by molecular, histological, biochemical and functional analyses. ResultsDysferlin abundance was markedly increased in HF fibroblasts. Across HF myocardium, DYSF was enriched in activated fibroblasts but largely excluded from COMP-enriched fibrotic regions, consistent with a role in restraining fibroblast state transitions. Although induced by TGF-{beta}, DYSF silencing enhanced extracellular matrix production, increased FOSL2 expression, and promoted differentiation into COMP-positive matrifibrocytes. In engineered human cardiac microtissues, DYSF silencing exacerbated fibrosis, increased apoptosis, and impaired contractility. Mechanistically, dysferlin restrained the TGF-{beta}-FOSL2-autophagy signalling axis, whereas FOSL2 suppressed DYSF expression, defining a reciprocal regulatory circuit. Silencing FOSL2 or MXRA5 increased dysferlin levels, while mRNA-protein discordance implicated S-acylation as a potential regulator of dysferlin protein abundance. ConclusionsDysferlin is a stress-inducible antifibrotic regulator that limits maladaptive fibroblast differentiation and myocardial fibrosis, thereby representing a potential therapeutic target to attenuate adverse cardiac remodelling in HF. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/745492v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@46ae02org.highwire.dtl.DTLVardef@4a0b99org.highwire.dtl.DTLVardef@13fa574org.highwire.dtl.DTLVardef@18777d4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Resolution of in situ inflammation in human lupus nephritis into principal immune cell trajectories

In human lupus nephritis (LuN), tubulointerstitial inflammation (TII) is prognostically more important than glomerular inflammation. However, a comprehensive understanding of both TII complexity and heterogeneity is lacking. Herein, we used high-dimensional confocal microscopy and specialized computer vision techniques to quantify immune cell populations and localize these within normal and diseased renal cortex structures. With these tools, we compared LuN to renal allograft rejection (RAR) and normal kidney. In both LuN and RAR, the 33 characterized immune cell populations formed discrete subgroups whose constituents co-varied in prevalence across biopsies. In both diseases, these co-variant immune cell subgroups organized into the same unique niches. Therefore, inflammation could be resolved into trajectories representing the relative prevalence and density of cardinal immune cell members of each co-variant subgroup. Indeed, in any one biopsy, the inflammatory state could be characterized by quantifying constituent immune cell trajectories. Remarkably, LuN heterogeneity could be captured by quantifying a few myeloid immune cell trajectories while RAR was more complex with additional T cell trajectories. Our studies identify rules governing renal inflammation and thus provide an approach for resolving LuN into discrete mechanistic categories. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/638655v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@109dd33org.highwire.dtl.DTLVardef@995037org.highwire.dtl.DTLVardef@161525dorg.highwire.dtl.DTLVardef@6692d8_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

immunology↗

bioRxiv2021

In lupus nephritis, specific in situ inflammatory states are associated with refractory disease and progression to renal failure

In human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to end stage renal disease (ESRD). However, while approximately half of patients with moderate or severe TII develop ESRD, half do not. Therefore, we hypothesized that TII is heterogeneous, with distinct inflammatory states associated with different renal outcomes. We interrogated renal biopsies from LN longitudinal and cross-sectional cohorts using both conventional and highly multiplexed confocal microscopy. To accurately segment cells across whole biopsies, and to understand their spatial relationships, we developed unique computational pipelines by training and implementing several deep learning models and other computer vision techniques. Surprisingly, across biopsies, high B cell densities were strongly associated with protection from ESRD. In contrast, elevated CD4-T cell population densities, which included CD8, {gamma}{delta} and double negative (CD4-CD8-{delta}-, DN) T cells, were associated with both acute refractory renal failure and gradual progression to ESRD. Interestingly, lymphocytes and dendritic cells were organized into discrete clusters or neighborhoods that could be characterized by the enrichment for specific cell populations. B cells were often organized into large neighborhoods with CD4+ T cells including T follicular helper-like cells. In contrast, the CD4-T cell populations formed small cellular neighborhoods whose frequency predicted subsequent progression to ESRD. These data reveal that in LN, specific in situ inflammatory states are associated with refractory disease and progression to ESRD. One sentence summaryUsing deep machine learning to analyze confocal microscopy data, we demonstrate that in lupus nephritis, CD4-T cell populations, including CD8+ and {gamma}{delta} T cells, organize into specific spatial neighborhoods that predict progression to renal failure.

immunology↗