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February 16, 2017

Epithelial Cells Put on the Rack to Extract Turnover Secrets

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    By sensing mechanical tensions, the transmembrane protein Piezo1 (red) helps trigger cell division or cell death, thereby maintaining healthy cell density. Division is triggered in the case of stretching (when cells are sparse). Cell expulsion, and subsequent cell death, is triggered in the case of crowding. [Swapna Gudipaty/Huntsman Cancer Institute]

    It was a stretch, but an investigation into epithelial cell turnover has revealed how cell division keeps pace with cell death. By subjecting epithelial cells to opposing mechanical tensions, scientists based at the Huntsman Cancer Institute (HCI) and at the University of Utah discovered that stretching causes cell division. Also, the scientists learned that crowding causes cell expulsion and death.

    The rate of cell division must match the rate of cell death if cell populations are to maintain healthy densities. If the division/death balance is off, inflammatory diseases or cancers can arise.

    “If too many epithelial cells die, you can lose their organ barrier function, and inflammatory diseases like asthma and colitis can result,” explained Jody Rosenblatt, Ph.D., an investigator at HCI, an associate professor of oncological sciences at the University of Utah, and the leader of the current study. “On the other hand, if too many cells divide compared to the number dying, this can cause an overabundance of cells, which can lead to tumor formation. So imbalance on either side is problematic.”

    Dr. Rosenblatt and colleagues published their findings February 15 in the journal Nature, in an article entitled “Mechanical Stretch Triggers Rapid Epithelial Cell Division through Piezo1.” The article describes how mammalian epithelial cell division occurs in regions of low cell density where cells are stretched.

    As the article’s title suggests, stretching stimulates cell division through activation of Piezo1, which is a large transmembrane protein. Piezo1, previous studies have speculated, might respond to changes in membrane curvature that occur because of alterations in cell shape. Conceivably, Piezo1 may sense changes in cell shape and membrane curvature that accompany cell stretching.

    “How Piezo1-dependent calcium transients activate two opposing processes may depend on where and how Piezo1 is activated, as it accumulates in different subcellular sites with increasing cell density,” wrote the authors of the Nature paper. “In sparse epithelial regions in which cells divide, Piezo1 localizes to the plasma membrane and cytoplasm, whereas in dense regions in which cells extrude, it forms large cytoplasmic aggregates.”

    Epithelial cells constitute the skin and skin-like linings that coat internal organs, giving organs a protective barrier so they can function properly. These linings, however, are also where about 90% cancers arise.

    Understanding what normally controls cell division and death, and how these processes are linked, is essential to understanding how these events become misregulated to drive cancer formation. While scientists had previously studied cell division and death in response to experimental triggers, how these processes naturally occur was less clear.

    "We knew there had to be some kind of regulation to tie the death and division processes together," noted Dr. Rosenblatt. "What we found boils down to really simple principles. It's all mechanical tension. If the cells get too crowded—1.6-fold more crowded—then they pop some cells out that later die. The extrusion of cells enables the cell sheets to return to densities they like."

    On the flip side, researchers noticed that cells divided in sparser areas. They realized those sparse regions were creating a tension on the cells to stretch.

    "If the cells become too sparse, then they activate cells to divide—and that signal to divide comes from mechanical stretch," continued Dr. Rosenblatt. "To test this, we stretched cells and found that stretch could trigger cells to divide within only 1 hour! The process also showed us that stretch is a normal trigger for cell division."

    Dr. Rosenblatt's team analyzed human colon cells, zebrafish cells, and dog cell cultures. The places where the cells divided were always more stretched out—1.6-fold more stretched out, just like the ratio for cell death.

    Besides implicating Piezo1 in the regulation of epithelial cell turnover, Dr. Rosenblatt’s team identified a stage in the cell cycle where cells sit paused for repair.

    “To stimulate cell division,” the authors of the Nature paper indicated, “stretch triggers cells that are paused in early G2 phase to activate calcium-dependent phosphorylation of ERK1/2 [extracellular signal-regulated protein kinases 1 and 2], thereby activating the cyclin B transcription that is necessary to drive cells into mitosis.”

    "We had always assumed that once cells start a division cycle, they just power through. We didn't know that they take breaks throughout the cell cycle," commented Dr. Rosenblatt. "But we found a point where the cells were just stalled, waiting to divide.

    “A lot of things need to happen for cells to divide. The DNA needs to replicate so it can divide in half, providing each new cell with the same DNA as the parent. These cells have everything ready to do that, but they still pause there at a step that we did not expect to be regulated."

    “Cells could be paused waiting to reach a certain size. Once they reach this size, stretch triggers them to divide."

    With the insight into how cells normally divide on their own, Dr. Rosenblatt believes scientists will have better insight into how epithelial cells divide when they shouldn't, like in cancer.

    "By understanding how cell death and division are normally regulated," she asserted, "we are discovering new ways that these processes go wrong—especially in diseases we don't currently have treatments for, things like asthma and metastatic cancers."

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