Anne Muesch, Ph.D.

Specialized tissue functions depend on cells building architectures that differ from generic epithelial or endothelial organization. Our research asks how cells interpret extracellular-matrix, adhesion, and mechanical cues to establish tissue-specific morphology and polarity, how these architectures are maintained during normal tissue use, and why they fail during injury, disease, and aging. We address these questions in liver sinusoidal endothelial cells, hepatocytes, and epithelial stress-response systems. Our studies use cell-biological approaches in primary cells, quantitative live- and fixed-cell imaging, and ultrastructural analysis to connect molecular signaling with membrane organization, cytoskeletal architecture, and cell function.

ECM-integrin control of liver sinusoidal endothelial fenestration: The liver sinusoidal endothelium contains transcellular pores, or fenestrae, that permit unusually efficient exchange between the blood and hepatocytes. Fenestrae are lost early in chronic liver disease and during aging, as liver sinusoidal endothelial cells acquire a capillary-like state and the normally sparse extracellular matrix becomes enriched in basement-membrane components. The central question is whether this matrix remodeling merely accompanies de-fenestration or actively instructs it. We are investigating how laminin-binding integrins and other ECM receptors regulate the membrane and cytoskeletal organization required for fenestra formation, and whether persistent ECM-integrin signaling prevents mature sinusoidal endothelial identity. Defining this relationship could explain why fenestration is difficult to restore once the sinusoidal niche has become fibrotic or aged and identify points at which the loss of endothelial specialization might be reversed.

ECM and adhesion control of hepatocyte polarity: Hepatocytes organize a branched bile-canalicular network between neighboring cells while simultaneously maintaining broad exchange surfaces facing the blood. This architecture is fundamentally different from the simple ducts and acini formed by most epithelia, yet the signals that specify it remain incompletely understood. Our work asks how the unusual ECM environment of the healthy liver cooperates with integrin and cell-cell adhesion signaling to orient hepatocyte junctions and build a continuous canalicular network. We further ask how fibrosis-associated changes in matrix composition, rigidity, and integrin expression distort this polarity program. The goal is to determine how disease converts a normally adaptive dialogue between cell-matrix and cell-cell adhesions into junctional arrangements that fragment or misdirect bile canaliculi, thereby impairing bile secretion and contributing to cholestasis and loss of liver function.

Borg5 control of epithelial architecture under mechanical stress: Cells in intact epithelia are continually compressed, stretched, and rearranged as tissues change density or respond to injury. We identified Cdc42EP1/Borg5, a regulator of septin and actin organization, as a candidate coordinator of the cellular response to these forces. We ask how junctional or mechanical stress controls Borg5 abundance and distribution, how Borg5 preserves apical surface organization, and why its loss compromises epithelial shape. A second, unexpected question is how Borg5 protects nuclear integrity and limits DNA damage through a mechanism that may be separable from its role in septin-actin organization. By resolving these functions, we aim to understand how epithelial cells buffer routine mechanical stress and why failure of this protective system may promote persistent injury, defective repair, and age-associated tissue decline.

1. Cohen D, Lázaro-Diéguez F, and Müsch A. Bile canaliculi formation in primary hepatocytes requires α1β1 integrin-dependent adherens junction re-organization. Journal of Cell Science 2025;138(23):jcs264412. doi:10.1242/jcs.264412.
2. Cohen D, Fernandez D, Lázaro-Diéguez F, Überheide B, and Müsch A. Borg5 restricts contractility and motility in epithelial MDCK cells. Journal of Cell Science 2024;137(23):jcs261705. doi:10.1242/jcs.261705.
3. Cohen D, Fernandez D, Lázaro-Diéguez F, and Müsch A. Par1b regulates epithelial lumen polarity via IRSp53-mediated cell-ECM signaling. Journal of Cell Biology 2011;192:525-540.
4. Lázaro-Diéguez F and Müsch A. Cell-cell adhesion accounts for the different orientation of columnar and hepatocytic cell divisions. Journal of Cell Biology 2017;216:3847-3859.
5. Cohen D, Rodriguez-Boulan E, and Müsch A. Par1 promotes a hepatic mode of apical protein targeting in MDCK cells. Proceedings of the National Academy of Sciences USA 2004;101:13792-13797.

Selected Reviews

1. Müsch A. From a common progenitor to distinct liver epithelial phenotypes. Current Opinion in Cell Biology 2018. doi:10.1016/j.ceb.2018.02.008.
2. Müsch A. The unique polarity phenotype of hepatocytes. Experimental Cell Research 2014;328(2):276-283.