I. Epithelial Homeostasis: Cell Division
II. Epithelial Apoptosis: Death by Epithelial Cell Extrusion
III. Pathologies Resulting From Aberrant Epithelial Extrusion
Part I: Epithelial Homeostasis: Cell Division
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|Resources: Related ArticlesRecorded: 2016|
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Both our entire body and all of our organs are covered with a protective layer of epithelial cells. These cells are constantly replicating and dying and a balance between cell death and division is critical to maintain epithelial homeostasis. Too much cell death can lead to gaps in the epithelial barrier while excess division can result in the formation of epithelial tumors. Rosenblatt is interested in understanding the signals that regulate epithelial homeostasis. In Part 1 of her talk, Rosenblatt describes her lab’s novel finding that stretching epithelial cells causes a stretch-activated Ca2+ channel (Piezo1) to open, increasing intracellular Ca2+ levels and stimulating pathways that trigger cell division.
How do epithelial cells die and not leave a hole in the protective membrane? In Part 2, Rosenblatt explains how her lab discovered epithelial cell extrusion or the process of squeezing dying cells out of the epithelial monolayer. Sphingosine 1-phosphate (S1P) is released by extruded cells and stimulates neighboring cells to form an actomyosin ring. Contraction of the ring squeezes out the apoptotic cell. Interestingly, crowding can activate extrusion of live cells that go on to die once they lose contact with other cells. Rosenblatt’s lab found that live, extruded cells also release S1P. S1P release is regulated by the same stretch activated channel, Piezo1, as is cell division. These data provide a mechanism by which epithelial barrier function and constant cell densities are maintained.
In her third talk, Rosenblatt describes how epithelial diseases such as asthma or cancer can result from aberrant cell extrusion. Too much cell extrusion can lead to holes in the epithelia and compromised barrier function, as seen in asthma. Too little extrusion can lead to masses of cells accumulating on epithelial surfaces, a process likely at work in some cancers. Rosenblatt also describes work from her lab that disrupted S1P signaling may play a key role in causing cancers of epithelial origin, such as pancreatic cancer. She also explains that extrusion from the basal face of an epithelial layer, rather than the usual apical extrusion, is likely an important first step in driving cancer metastasis.
Dr. Jody Rosenblatt received her BA with honors from the University of California, Berkeley and, after a short stint at Chiron Corporation, she moved across the bay to work as a technician with David Morgan at the University of California, San Francisco. Rosenblatt stayed on at UCSF for her PhD where she worked in Tim Mitchison’s lab. She then moved to University College London for post-doctoral training. It was at UCL that Rosenblatt discovered extrusion and its role in epithelial homeostasis.
Currently, Rosenblatt is an Associate Professor in the Department of Oncological Sciences at the University of Utah School of Medicine and an Investigator of the Huntsman Cancer Institute. Her lab studies cell death and division in epithelia.
Learn more about Dr. Rosenblatt’s research here.
- Mary Beckerle iBioSeminar: Adhesion, Signaling and Cancer
Rosenblatt J, Raff MC, Cramer LP (2001). An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr Biol, 11(23), 1847-57.
Gu Y, Forostyan T, Sabbadini R, Rosenblatt J (2011). Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway. J Cell Biol, 193(4), 667-76.
Eisenhoffer GT, Loftus PD, Yoshigi M, Otsuna H, Chien CB, Morcos PA, Rosenblatt J (2012). Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia. Nature, 484(7395), 546-9.
Gu Y, Shea J, Slattum G, Firpo MA, Alexander M, Mulvihill SJ, Golubovskaya VM, Rosenblatt J (2015). Defective apical extrusion signaling contributes to aggressive tumor hallmarks. eLife, 4, e04069.
Eisenhoffer GT, Rosenblatt J (2013). Bringing balance by force: live cell extrusion controls epithelial cell numbers. Trends Cell Biol, 23(4), 185-92.
Slattum GM, Rosenblatt J (2014). Tumour cell invasion: an emerging role for basal epithelial cell extrusion. Nat Rev Cancer, 14(7), 495-501.
Gudipaty SA, Rosenblatt J (2016). Epithelial cell extrusion: Pathways and pathologies. Semin Cell Dev Biol.