Biology subjects

Zeck, B.

Publications and source records attributed to Zeck, B..

3 recordsLinked to original sources

bioRxiv2025

An immunocompetent murine model of virus-elicited liver fibrosis and hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third deadliest cancer worldwide. Over 75% of HCC cases are associated with chronic viral infections. Mechanistic studies and preclinical therapeutic development for virus-associated HCC have been limited by a paucity of small animal models of chronic hepatotropic virus infection that faithfully recapitulate human disease. Here we demonstrate the induction of chronic hepatitis, progressive liver fibrosis, and HCC in immunocompetent laboratory mice upon chronic viral infection with Norway rat hepacivirus (NrHV) - a virus closely related to hepatitis C virus (HCV). NrHV-elicited tumors resemble HCV-associated tumors and liver transcriptome analyses reveal numerous similarities between chronic NrHV and HCV. These findings establish an experimentally tractable, physiologically relevant, and immunocompetent mouse model of virus-elicited progressive liver fibrosis and oncogenesis.

pathology↗

bioRxiv2020

Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic steatohepatitis development in chimeric mice

Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of chimeric mice respond to a hypercaloric Western-style diet. As early as 4 weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatohepatitis selectively in the human graft, followed by pericellular fibrosis after 8 weeks of hypercaloric feeding. The PNPLA3 148M variant, either from a homozygous 148M human donor or overexpressed in a homozygous 148I donor background, caused widespread microvesicular steatosis and even more severe steatohepatitis. We conclude that PNPLA3 148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variants associated with advanced fatty liver diseases.

pathology↗

bioRxiv2020

Interstitial spaces are continuous across tissue and organ boundaries in humans

Bodies have "reticular networks" comprising collagens, elastin, glycosaminoglycans, and other extracellular matrix components, that are continuous within and around all organs. Fibrous tissue coverings of nerves and blood vessels create structural continuity beyond organ boundaries. We recently described fluid flow through such human fibrous tissues. It remains unclear whether these interstitial spaces are continuous through the body or are discontinuous, confined within individual organs. We investigated IS continuity using two approaches. Non-biological particles (tattoo pigment, colloidal silver) were tracked within colon and skin interstitial spaces and into adjacent fascia. We also exploited hyaluronic acid, a macromolecular component of interstitial spaces. Both techniques demonstrate continuity of interstitial spaces within and across organ boundaries, including within perineurium and vascular adventitia traversing organs and the spaces between them. We suggest a body-wide network of fluid-filled interstitial spaces with significant implications for molecular signaling, cell trafficking, and the spread of malignant and infectious disease.

pathology↗