The Role of Extrusion in Controlling Epithelial Homeostasis

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DESCRIPTION (provided by applicant): 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.