Anne Muesch, Ph.D.

We are elucidating molecular mechanisms that determine cell morphology and polarity.
Specifically, we are addressing two unresolved key questions in liver development, injury, and aging:

1) Mechanisms underlying endothelial fenestration: The liver filters metabolites, hormones, and toxins from the blood for processing, de-toxification and storage, while delivering major plasma proteins such as albumin, clotting factors and transferrin into the circulation. This exchange takes place between hepatocytes, the livers parenchymal epithelial cells, and Liver Sinusoidal Endothelial Cells (LSECs), which form small sinusoidal blood vessels adjacent to hepatocytes. The extraordinary volume of molecular exchange between epithelial and endothelial cells in the liver is unmatched by other organs; it is enabled by lack of an obstructive basement membrane between hepatocytes and LSECs and by open cell-spanning pores (fenestrae) in LSECs, which allow free diffusion of molecules in and out of blood vessels. Loss of LSEC fenestrae is an early hallmark of common liver diseases and is a characteristic of the normal aging liver; age-related dyslipidemia and insulin resistance in old age have been attributed to changes in the microcirculation caused by loss of LSEC fenestrae. How fenestrae form and why fenestration diminishes with age is not known. We are utilizing live and fixed cell imaging and electron microscopic approaches in primary LSECs to test hypotheses regarding the membrane-remodeling processes leading to their fenestration.

2) The unique epithelial polarity phenotype of hepatocytes: Hepatocytes, the liver’s parenchymal cells, acquire an epithelial architecture that is unique among epithelia and is superbly adapted to their functions: Unlike most epithelia, which organize as monolayered ducts or acini, hepatocytes arrange in cords aligned with fenestrated blood vessels on either side and with a capillary-like luminal network (bile canaliculi) running between them. This organization facilitates hepatocytes’ extensive bi-directional molecular exchange with the blood, while allowing excretion of bile acids (digestive aids), into the bile canaliculi for drainage into bile ducts. Common liver diseases such as cirrhosis and hepatocellular carcinoma present with defects in hepatocyte polarity, impairing metabolic functions and causing cytotoxic interstitial bile accumulation (cholestasis), making it imperative to understand their molecular basis. Yet, how hepatocytes obtain their unique morphological phenotype and why it becomes disrupted in disease remains largely unknown. To tackle these questions, we developed a unique tissue culture model in which the polarity phenotype can be switched from ductal to hepatocytic. It allowed us to identify crosstalk between Extracellular Matrix (ECM) and cell-cell adhesion signaling as critical determinant for the hepatocytic versus ductal polarity decision. We are now modeling ECM deposition and integrin expression changes characteristic of common liver diseases in primary hepatocyte cultures to investigate molecularly how the resulting alterations in cell-matrix adhesion affect hepatocyte polarity and the integrity of the bile canaliculi network.

Selected Publications:

Lázaro-Diéguez F, Müsch A. (2022). Live-cell Imaging of Biosynthetic Protein Transport in   Hepatocytes. In: Tanimizu, N. (eds) Hepatocytes. Methods in Molecular Biology, vol 2544.  Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2557-6_10

Lázaro-Diéguez F, Müsch A. Low Rho activity in hepatocytes prevents apical from basolateral cargo separation during trans-Golgi network to surface transport. Traffic 2020 May;21(5):364-374

Lázaro-Diéguez F, Müsch A. “ Cell-cell adhesion accounts for the different orientation of columnar and hepatocytic cell divisions”, J Cell Biol. 2017 216(11):3847-3859.

Treyer, A., Pujato, M, Pechuan, X and Müsch, A. “Iterative sorting of apical and basolateral cargo in MDCK cells”. Mol. Biol. Cell  2016 27(14):2259-71

Lázaro-Diéguez F, Ispolatov I, Müsch A. Cell shape impacts on the positioning of the mitotic spindle with     respect to the substratum. Mol Biol. Cell, 2015,. Apr 1;26(7):1286-95

Lazaro-Dieguez, F. Cohen D., Fernandez D., Louis Hodgson, S. van IJzendoorn and Müsch, A. “Par1b links lumen polarity with LGN/NuMA positioning for distinct epithelial cell division phenotypes”, (2013) J Cell Biol. 203(2): 251-64

Ispolatov I, Müsch, A. " A model for the self-organization of vesicular flux and protein distributions in the Golgi apparatus", (2013), PLOS Computational Biology, Jul;9(7):e1003125. doi: 10.1371/journal.pcbi.1003125

Cohen D., Fernandez D., Lazaro-Dieguez, F. and Anne Müsch,. “The serine/threonine kinase Par1b regulates epithelial lumen polarity via IRSp53-mediated cell-ECM signaling”, (2011) J Cell Biol. 192, 525-540.

Cohen, D., Rodriguez-Boulan, E. and  Müsch, A. (2004). "Par-1 promotes a   hepatic mode of apical protein trafficking in MDCK cells". PNAS 101, 13792-97.

Cohen, D., Brennwald, P.J., Rodriguez-Boulan, E.  and Müsch, A.  (2004)."Mammalian PAR-1 determines epithelial lumen polarity by organizing the microtubule cytoskeleton". Journal Cell Biology, 164, 717-727.

Zamperone A, Cohen D, Stein M, Viard C, Müsch A. Inhibition of polarity-regulating kinase PAR1b contributes to Helicobacter pylori- inflicted DNA Double Strand Breaks in gastric cells. Cell Cycle. 2019 Feb;18(3):299-311.

Mishra JP Cohen D, Zamperone A, Nesic D, Muesch A, Stein M. CagA of Helicobacter pylori interacts with and inhibits the serine-threonine kinase PRK2. Cellular microbiology. 2015; 17(11):1670-82.

Zaher Zeaiter, David Cohen, Anne Müsch, Fabio Bagnoli, Antonello Covacci, and Markus Stein (2008) "Analysis of detergent resistant membranes of Helicobacter pylori infected gastric adenocarcinoma cells reveals a role for MARK2/Par1b in CagA-mediated disruption of cellular polarity",  J Cellular Microbiology, 10, 781-94.

Reviews and Book Chapters:

Müsch A. and  Arias I “Hepatoyte Surface Polarity” in:  The Liver: Biology and  Pathobiology,  Sixth Edition, Edts: Arias et al., 2020 Print ISBN:9781119436829 Wiley &Sons Ltd

Müsch, A. 2018. From a common progenitor to distinct liver epithelial phenotypes. Current opinion in cell biology. 54:18-23.

Müsch, A. Vesicular Transport in the Secretory and Endocytic Pathways, e-book in Colloquim Series on Building Blocks of the Cell: Cell Structure and FunctionMorgan & Claypool Life Sciences September 2014, 125 pages, (doi:10.4199/C0011ED1V01Y201407BBC008)

Müsch, A. “The unique  polarity phenotype of hepatocytes” Exp. Cell Research 2014. 328(2):276-83.

Treyer A., Müsch, A. “Hepatiocyte Polarity” , (2013) Comprehensive Physiology, 3, 243-87.

Rodriguez-Boulan, E., Kreitzer G and Müsch, A.  (2005) "Protein Sorting and Post-Golgi Trafficking in Epithelia."Nature Reviews Molecular Cell Biology, 6, 233-47

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