Biology subjects

Muhl, L.

Publications and source records attributed to Muhl, L..

5 recordsLinked to original sources

bioRxiv2025

A comprehensive molecular atlas of the cell types in the mouse liver

The liver plays a crucial role in essential physiological processes, and its impaired function due to liver fibrosis from various causes is an increasingly significant health issue. The livers functionality relies on the precise arrangement of its cellular structures, yet the molecular architecture of these units remains only partially understood. We created a comprehensive molecular atlas detailing all the major cell types present in the adult mouse liver through deep single-cell RNA sequencing. Our analysis offers new insights into hepatic endothelial and mesenchymal cells, specifically highlighting the differences between the cells of the periportal microvasculature, the sinusoids, and the portal vein, the latter exhibiting a mixed arterio-venous phenotype. We identified distinct subpopulations of hepatic stellate cells, fibroblasts, and vascular mural cells located in different anatomical regions. Comparisons with transcriptomic data from disease models indicate that a previously unrecognized capsular population of hepatic stellate cells expands in response to fibrotic disease. Our findings reveal that various fibroblast subpopulations respond differently to pathological insults. This data resource will be invaluable for advancing therapeutic interventions targeting hepatic diseases.

cell biology↗

bioRxiv2024

Thrombolysis exacerbates cerebrovascular injury after ischemic stroke via a VEGF-B dependent effect on adipose lipolysis

Cerebrovascular injuries leading to edema and hemorrhage after ischemic stroke are common. The mechanisms underlying these events and how they are connected to known risk factors for poor outcome, like obesity and diabetes, is relatively unknown. Herein we demonstrate that increased adipose tissue lipolysis is a dominating risk factor for the development of a compromised cerebrovasculature in ischemic stroke. Reducing adipose lipolysis by VEGF-B antagonism improved vascular integrity by reducing ectopic cerebrovascular lipid deposition. Thrombolytic therapy in ischemic stroke using tissue plasminogen activator (tPA) leads to increased risk of hemorrhagic complications, substantially limiting the use of thrombolytic therapy. We provide evidence that thrombolysis with tPA promotes adipose tissue lipolysis, leading to a rise in plasma fatty acids and lipid accumulation in the ischemic cerebrovasculature after stroke. VEGF-B blockade improved the efficacy and safety of thrombolysis suggesting the potential use of anti-VEGF-B therapy to extend the therapeutic window for stroke management.

neuroscience↗

bioRxiv2021

Reduced myofibroblast transdifferentiation and fibrotic scarring in ischemic stroke after imatinib treatment

The tyrosine kinase inhibitor imatinib has been reported to improve outcome in patients following ischemic stroke but the exact mechanism remains elusive. Here, utilizing a photothrombotic murine model of middle cerebral artery occlusion (MCAO), we show that imatinib-mediated inhibition of stroke-induced blood-brain barrier (BBB) dysfunction coincided with decreased expression of genes associated with inflammation and fibrosis in the cerebrovasculature. We found that imatinib effectively dampened stroke-induced reactive gliosis and myofibroblast transdifferentiation, whilst having very limited effect on the rest of the glia scar and on peripheral leukocyte infiltration. Further, our data suggest that consolidation of the PDGFR+ portion of the fibrotic scar in imatinib-treated mice contributes to the improvement in functional outcome compared to the vehicle controls, where the PDGFR+ scar is expanding. Comparison with human stroke transcriptome databases revealed significant overlap with imatinib-regulated genes, suggesting imatinib may modulate reactive gliosis and fibrotic scarring also in human stroke.

neuroscience↗

bioRxiv2020

Lack of evidence of ACE2 expression and replicative infection by SARS-CoV-2 in human endothelial cells

A striking feature of severe COVID-19 is thrombosis in large as well as small vessels of multiple organs. This has led to the assumption that SARS-CoV-2 virus directly infects and damages the vascular endothelium. However, endothelial expression of ACE2, the cellular receptor for SARS-CoV-2, has not been convincingly demonstrated. Interrogating human bulk and single-cell transcriptomic data, we found ACE2 expression in endothelial cells to be extremely low or absent in vivo and not upregulated by exposure to inflammatory agents in vitro. Also, the endothelial chromatin landscape at the ACE2 locus showed presence of repressive and absence of activation marks, suggesting that the gene is inactive in endothelial cells. Finally, we failed to achieve infection and replication of SARS-CoV-2 in cultured human endothelial cells, which were permissive to productive infection by coronavirus 229E that uses CD13 as the receptor. Our data suggest that SARS-Cov-2 is unlikely to infect endothelial cells directly; these findings are consistent with a scenario where endothelial injury is indirectly caused by the infection of neighbouring epithelial cells and/or due to systemic effects mediated by immune cells, platelets, complement activation, and/or proinflammatory cytokines.

pathology↗

bioRxiv2020

Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 - implications for microvascular inflammation and hypercoagulopathy in COVID-19 patients

Accumulating clinical observations implicate vascular inflammation as an underlying cause of coagulopathy in severely ill COVID-19 patients and it was recently suggested that SARS-CoV-2 virus particles infect endothelial cells. Here, we show that endothelial cells do not express angiotensin-converting enzyme-2 (ACE2), the SARS-CoV-2 receptor. Instead, pericytes and microvascular smooth muscle cells express ACE2 in an organotypic manner. Pericyte deficiency leads to increased endothelial expression and release of Von Willebrand factor and intravascular platelet and fibrin aggregation, suggesting that pericytes limit endothelial pro-thrombotic responses. That pericytes and not endothelial cells express ACE2 may provide important clues to the pathology of COVID-19, as pericytes are normally shielded behind an endothelial barrier and may get infected only when this barrier is compromised by COVID-19 risk factors.

pathology↗