Epithelial cells work together to form a protective layer for all the organs they encase yet they turnover through cell death and division at some of the highest rates in the body. To maintain a functional barrier and prevent solid tumors from arising, the numbers of cells that die must match those that divide. We found that mechanical tensions control both processes: when cells are too sparse, stretch rapidly activates cell division, whereas, when cells are too abundant, crowding activates cell extrusion and death. Astonishingly, we identified that a single stretch-activated channel, Piezo1, controls both stretch-induced cell division and crowding-induced cell extrusion. Within only one hour of stretch, Piezo1 activates a population of epithelial cells poised in G2 to accumulate cyclin B and enter mitosis. Conversely, during crowding, Piezo1 activates cells to produce and emit a lipid, Sphingosine 1-Phosphate (S1P), which binds a G-Protein Coupled Receptor in the neighboring cells, S1P2, which activates Rho-mediated actomyosin contraction to squeeze the cell out apically, while maintaining a tight barrier. While apoptotic signaling activates extrusion of dying cells, normally, Piezo1 senses crowding to activate extrusion of live cells that later die by anoikis, or apoptosis due to loss of survival signaling. In this proposal, we investigate how Piezo1 activates cells to divide or extrude and die, depending on the type of force it senses. Piezo1 localizes to the nuclear envelope, ER, and plasma membrane in sparser epithelial regions most likely to divide, and then accumulates into large cytoplasmic plaques in crowded, older cells most likely to extrude. Thus, we propose that Piezo1 can sense stretch in places that need to generate more cells and sense crowding in places that need to eliminate cells through its localization. In our grant renewal, we investigate if Piezo1 levels and localization in sparse versus crowded cells control Ca+2 activation of differential targets to drive cell division or extrusion, respectively. Here we investigate: 1) How does Piezo1 promote extrusion in crowded regions of epithelia? 2) Does calcium activate S1P formation or inactivate adhesion (or other) complexes? 3) How does Piezo1 trigger cell division in sparser epithelial regions? We believe the answers to these questions will give us a better understanding of how cell division and death are governed in epithelia. We also expect our findings to have much broader implications in cancer and other epithelial-based diseases, since we have found that different diseases appear to hijack every facet of extrusion signaling we have identified so far. Thus, uncovering the fundamental pathways that control cell death and division will give us a unique edge is discovering new approaches to treat diseases resulting from their misregulation.

Public Health Relevance

Epithelial cells turnover at some of the fastest rates in the body, yet must maintain constant numbers to preserve a functional barrier for the organs they encase and to prevent carcinoma formation. We have discovered that mechanical tensions control both cell death and division: when cells are too sparse, stretch rapidly activates cells to divide, when there too many, crowding activates cells to extrude and die. We found that a single stretch-activated channel, Piezo1, controls both stretch-activated division and crowding-induced extrusion and, here, investigate how it controls these opposing processes in response to opposing forces.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM102169-07
Application #
9552184
Study Section
Intercellular Interactions Study Section (ICI)
Program Officer
Deatherage, James F
Project Start
2012-08-01
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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