Faculty Profile

Dr. Anne Muesch, Ph.D.

Anne Muesch, Ph.D.

Professor, Department of Developmental & Molecular Biology

Areas of Research: Epithelial cell biology: 1) What causes the distinct epithelial architecture of tubule-forming bile duct cells and hepatocytes in the liver? 2) Why does Helicobacter pylori infection poses a gastric cancer risk?

Professional Interests

We are using cell biological approaches and stem-cell derived epithelial organoid cultures to understand signaling mechanisms that govern the establishment and maintenance of epithelial cell polarity and their relevance for morphogenesis and cell transformation. 

1. Mechanisms for the establishment of the two distinct epithelial phenotypes in the liver

The liver is our largest metabolic organ. It produces proteins, lipids, clotting factors and glycogen while dispensing bile and detoxifying xenobiotics. In order to transport these different substances, a sophisticated network of liver venules, capillaries and interstitial conduits has evolved. An essential feature of this network are the lumen-forming epithelia that give rise to two major liver cell populations: (1) mature hepatocytes - the main parenchymal cell type, and (2) bile duct cells. Hepatocytes form single-cell cords with a capillary-like luminal network (bile canaliculi) running between them. In contrast, bile duct cells form tubules, each with a central lumen that receives the content of the bile canaliculi that has formed next to hepatocytes. During initial liver development and bouts of regeneration, both hepatocytes and bile duct cells are derived from a common epithelial precursor. How hepatocytes and biliary epithelia obtain their unique morphological and functional phenotypes from this common precursor is poorly understood. Indeed, because bile canaliculi are not readily visible by conventional H&E tissue stain, the study of epithelial polarity in the liver has largely been neglected.  The resulting gap in our knowledge has greatly hindered our ability to better understand the molecular basis of common liver diseases, which typically present with changes in lumen organization. It also severely limits our ongoing efforts to engineer hepatic tissue that can be used for transplantation, toxicology and gene therapy studies. To tackle these issues, we have developed a unique tissue culture model in which we polarize an epithelial cell line with either hepatocytic or ductal polarity. It allowed us formulate hypotheses on how these two major epithelial phenotypes arise, implicating cell adhesion signaling and protein trafficking as key determinants. We are testing our hypotheses and elucidate their molecular details in primary and organoid-derived liver cells.

 

2. Identification of Par1b signaling pathways in epithelial cells - The role of Par1b in H. pylori pathology

Par1 isoforms are serine/threonine kinases that have emerged as  "core determinants" of cell polarity in different contexts, including in mammalian epithelial cells. In collaboration with the microbiologist M. Stein (then Univ Edmonton, Alberta) we found that Par1b is inactivated by the cytotoxic protein CagA of Helicobacter pylori. H. pylori is a human adapted bacterium that colonizes the gastric mucosa of an estimated half of the worlds’ population and destroys the epithelial lining of the stomach in a fraction of infected carriers, resulting in gastritis and gastric ulcers. H. pylori induced gastric atrophy can progress to  gastric cancer, and CagA has been classified as a bacterial oncogene by the WHO. We are elucidating CagA signaling mechanisms that are mediated by Par1b inhibition. In addition to the effects on epithelial morphology and cell-cell junctional integrity we identified a contribution of Par1b-inhibition to the accumulation of DNA doublestrand breaks in H.p. infected gastric epithelium. Since repair of these lesions is error-prone,  they likely contribute to the transformation risk. To identify relevant Par1b- substrates we have conducted an unbiased screen that yielded more than 70 putative novel Par1b substrates and their Par1b phosphorylation sites in polarized epithelial cells. We are investigating their roles in H. pylori infected gastric epithelial monolayers derived from organoids, which we establish from human tissue that is leftover from bariatric surgery. 

 

 

Selected Publications

Selected Publications:

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.

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.

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.

Reviews:

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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Research Information