Biology subjects

Ramm, G. A.

Publications and source records attributed to Ramm, G. A..

5 recordsLinked to original sources

bioRxiv2026

Mapping fibrotic microenvironments: single-cell and spatial profiling of Schistosoma mansoni-induced tissue fibrosis

Schistosoma-induced tissue fibrosis, driven by immune response to trapped schistosome eggs, is the principal cause of pathology and schistosomiasis-related morbidity. While praziquantel effectively clears adult parasites, no therapies exist to target eggs or egg-induced tissue fibrosis. Here, we utilise single-cell spatial transcriptomics to define the high-resolution molecular architecture of the fibrotic niche in Schistosoma mansoni-infected mice at 8 weeks post-infection. Our data reveal that the host executes divergent, organ-specific biological programs: constructing a rigid, concentric fibrotic granuloma for permanent egg sequestration in the liver while building a flexible, discontinuous collagen architecture in the intestine to facilitate egg transit. Spatially resolved cell-cell interaction analysis, unprecedented in schistosome-induced fibrosis, identifies the strongest cellular interactions between macrophages and collagen-producing cells, with TGF-{beta}-dominant ligand-receptor pairs in the hepatic niche and integrin-centered pairs in the intestine. Despite this architectural divergence, we detected a core signature of five ligand-receptor pairs shared across both tissues, suggesting shared signalling interactions that could be leveraged for pan-tissue therapeutics for treating schistosome-induced fibrosis. Together, these findings provide the first high-resolution spatial atlas of schistosomiasis-associated fibrosis and provide a foundational framework for discovering novel drug targets capable of reversing established tissue damage, addressing a critical clinical gap where current therapies fail.

molecular biology↗

bioRxiv2024

A non-catalytic function of a disintegrin and metalloprotease 10 determines hepatic progenitor cell fate

During chronic liver disease, hepatocytes may undergo proliferative arrest, leading to the activation, expansion and differentiation of hepatic progenitor cells (HPCs). Here we observe that expression of A Disintegrin And Metalloprotease (ADAM) 10 is increased in human and murine chronic liver disease correlating with HPC expansion. We report that proteolytic processing of ADAM10 by ADAM9 and generation of an ADAM10 intracellular domain that translocates to the nucleus, rather than ADAM10 enzymatic activity is essential for the regulation of HPC gene expression and differentiation. Genetic loss of ADAM10 in vitro and in vivo enhances stemness gene expression, increases the accumulation of undifferentiated HPCs and promotes the formation of liver fibrosis. Taken together, we demonstrate that a non-catalytic function of ADAM10 is an essential regulator of HPC fate and HPC-driven regeneration. Our data ascribe a non-proteolytic function to ADAM proteases which may be a general concept in adult tissue stem cells.

cell biology↗

bioRxiv2024

A maternal high-fat diet predisposes to infant lung disease via increased neutrophil-mediated IL-6 trans-signaling

Poor maternal diet during pregnancy predisposes to severe lower respiratory tract infections (sLRI) in infancy, which in turn, increases childhood asthma risk, however the underlying mechanisms remain poorly understood. Here, we show that the offspring of high fat diet (HFD)-fed mothers ( HFD-reared pups) developed a sLRI following pneumovirus inoculation in early-life and subsequent asthma in later-life upon allergen exposure. Prior to infection, HFD-reared pups developed microbial dysbiosis and low-grade systemic inflammation (LGSI), characterized by hyper-granulopoiesis in the liver and elevated inflammatory cytokine expression, most notably IL-17A, IL-6 and sIL-6R (indicative of IL-6 trans-signaling) in the circulation and multiple organs, but most prominently the liver. Inhibition of IL-6 trans-signaling, using sgp130Fc transgenic mice or via specific genetic deletion of IL-6Ra on neutrophils, conferred protection against both diseases. Taken together, our findings suggest that a maternal HFD induces neonatal LGSI that predisposes to sLRI and subsequent asthma via neutrophil-mediated IL-6 trans-signaling.

immunology↗

bioRxiv2022

Single Nucleus RNA Sequencing of Pre-Malignant Liver Reveals Disease-Associated Hepatocyte State with HCC Prognostic Potential

Current approaches to stage chronic liver diseases have limited utility to directly predict liver cancer risk. Here, we employed single nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and chronically injured pre-malignant livers using two distinct mouse models. Analysis of 40,748 hepatic nuclei unraveled a previously uncharacterized disease-associated hepatocyte transcriptional state (daHep). These cells were absent in healthy livers, but were increasingly prevalent as chronic liver disease progressed towards hepatocarcinogenesis. Gene expression deconvolution of 1,439 human liver transcriptomes from publicly available datasets revealed that daHep frequencies highly correlate with current histopathological liver disease staging systems. Importantly, we show that high daHep levels precede carcinogenesis in mice and humans and predict a higher risk of hepatocellular carcinoma (HCC) development. This novel transcriptional signature with diagnostic and, more importantly, prognostic significance has the potential to change the way chronic liver disease patients are staged, surveilled and risk-stratified.

cancer biology↗

bioRxiv2021

Therapeutic potential of macrophage colony-stimulating factor (CSF1) in chronic liver disease

Resident and recruited macrophages control the development and proliferation of the liver. We showed previously in multiple species that treatment with a macrophage colony stimulating factor (CSF1)-Fc fusion protein initiated hepatocyte proliferation and promoted repair in models of acute hepatic injury in mice. Here we investigated the impact of CSF1-Fc on resolution of advanced fibrosis and liver regeneration, utilizing a non-resolving toxin-induced model of chronic liver injury and fibrosis in C57BL/6J mice. Co-administration of CSF1-Fc with exposure to thioacetamide (TAA) exacerbated inflammation consistent with monocyte contributions to initiation of pathology. After removal of TAA, either acute or chronic CSF1-Fc treatment promoted liver growth, prevented progression and promoted resolution of fibrosis. Acute CSF1-Fc treatment was also anti-fibrotic and pro-regenerative in a model of partial hepatectomy in mice with established fibrosis. The beneficial impacts of CSF1-Fc treatment were associated with monocyte-macrophage recruitment and increased expression of remodeling enzymes and growth factors. These studies indicate that CSF1-dependent macrophages contribute to both initiation and resolution of fibrotic injury and that CSF1-Fc has therapeutic potential in human liver disease. Summary statementMacrophages contribute to both progression and resolution of chronic tissue injury and fibrogenesis. Administration of a macrophage growth factor promoted liver regeneration and resolution of advanced liver fibrosis in mice.

immunology↗