The role of cell stretch for inducing proliferation in epithelia provide a protective barrier for the organs they encase;yet cells comprising this barrie are constantly renewed via cell death (apoptosis) and division. Surprisingly little is known about what triggers cells to naturally divide or die or how the number of cells dying and dividing are balanced during homeostasis. If the death rate becomes higher, barrier function diseases such as asthma may result and if the division rate is higher, solid tumors may result. Previously, we found that epithelia match cell death with cell division mechanically through crowding. Epithelial crowding forces from cells accumulating through division and migration act to shove cells out, through a process I discovered termed cell extrusion. Blocking any step of the crowding-induced extrusion pathway that we defined leads to epidermal masses in zebrafish, confirming its critical role for controlling epithelial cell turnover in vivo. While the parent grant investigated how too many cells, manifested by cell crowding, can lead to extrusion-dependent cell death, here, we examine how too few cells within an epithelium, manifested by cell stretching, can lead to production of more cells by cell division. Cell stretching during developmental morphogenesis or wound healing cells frequently occurs prior to a wave of proliferation. We recently found that stretching contact-inhibited epithelial monolayers leads to rapid cell proliferation (within one hour), independently of wound or developmental signals. Because mitosis occurs so rapidly, we predict that these cells initiate division from the G2 phase of the cell cycle, despite starting frm a state usually associated with quiescence. Gadolinium addition block mitosis following stretch, suggesting that stretch-activated channels translate stretch into mitosis. To understand how stretch translates into mitogenic signaling, we will test the following in this revision grant: 1) est from which point(s) in the cell cycle cells initiate proliferation following stretch and 2) identif signals that translate cell stretch into proliferation by testing candidates from the literature an a proteomic screen. Once we identify how stretch activates cells to proliferate, we will test if this same signaling regulates division during normal homeostasis. If so, cell growth could similarly cause stretching of the membrane to trigger mitosis and reveal the elusive link between cell growth and division. Having developed many tools in our parent grant, we feel we are well poised to make rapid strides in identifying this fundamental pathway for regulating cell division. The proposed research is innovative because it examines a novel mechanism for how epithelial cells maintain homeostatic cell numbers, which may also reveal how cells link growth with division. It also uses multidisciplinary approaches, including a zebrafish epidermal model we developed to study epithelia and a cell stretch device we developed with a bioengineer. The proposal is medically significant because misregulation of epithelial homeostasis is likely at the heart of most solid tumor formation and barrier function diseases.

Public Health Relevance

Epithelia monolayers or bilayers coat and protect organs within the body, preserving their identity and function. Epithelial cells constantly turn over by cll division and death, yet little is known about how these rates are linked, despite the fact that controlling this link is critical for preventing tumor formation and barrier diseases. We have recently found that when epithelial cell numbers become too sparse and stretch, they trigger cells to rapidly divide to replenish cell numbers.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZGM1-CBB-0 (MI))
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Deatherage, James F
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University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
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Eisenhoffer, George T; Slattum, Gloria; Ruiz, Oscar E et al. (2016) A toolbox to study epidermal cell types in zebrafish. J Cell Sci :
Gudipaty, Swapna Aravind; Rosenblatt, Jody (2016) Epithelial cell extrusion: Pathways and pathologies. Semin Cell Dev Biol :
Gu, Yapeng; Shea, Jill; Slattum, Gloria et al. (2015) Defective apical extrusion signaling contributes to aggressive tumor hallmarks. Elife 4:e04069
Slattum, Gloria; Gu, Yapeng; Sabbadini, Roger et al. (2014) Autophagy in oncogenic K-Ras promotes basal extrusion of epithelial cells by degrading S1P. Curr Biol 24:19-28
Slattum, Gloria M; Rosenblatt, Jody (2014) Tumour cell invasion: an emerging role for basal epithelial cell extrusion. Nat Rev Cancer 14:495-501
Eisenhoffer, George T; Rosenblatt, Jody (2013) Bringing balance by force: live cell extrusion controls epithelial cell numbers. Trends Cell Biol 23:185-92
Gu, Yapeng; Rosenblatt, Jody (2012) New emerging roles for epithelial cell extrusion. Curr Opin Cell Biol 24:865-70
Rosenblatt, Jody (2012) Programmed cell death: a new way worms get rid of unwanted cells. Curr Biol 22:R844-6