Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
The Journal of Cell Biology (Impact Factor: 9.69). 05/2011; 193(4):667-76. DOI: 10.1083/jcb.201010075
Source: PubMed

ABSTRACT To maintain an intact barrier, epithelia eliminate dying cells by extrusion. During extrusion, a cell destined for apoptosis signals its neighboring cells to form and contract a ring of actin and myosin, which squeezes the dying cell out of the epithelium. Here, we demonstrate that the signal produced by dying cells to initiate this process is sphingosine-1-phosphate (S1P). Decreasing S1P synthesis by inhibiting sphingosine kinase activity or by blocking extracellular S1P access to its receptor prevented apoptotic cell extrusion. Extracellular S1P activates extrusion by binding the S1P(2) receptor in the cells neighboring a dying cell, as S1P(2) knockdown in these cells or its loss in a zebrafish mutant disrupted cell extrusion. Because live cells can also be extruded, we predict that this S1P pathway may also be important for driving delamination of stem cells during differentiation or invasion of cancer cells.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: eLife digest Epithelial cells cover the surface of our bodies, line our lungs, stomach and intestines and serve as a protective layer around other organs. If too many epithelial cells die and are not replaced, this protective layer may erode and lead to organ damage. However, if too many new cells grow, tumors can form. One process that helps to maintain the right number of epithelial cells is called extrusion. When too many epithelial cells are present, the resulting overcrowding triggers this process to squeeze excess cells out of the layer and away from the organ. Usually, these cells quickly die. However, if the pathway that regulates this process—which involves a receptor protein called S1P2—is disturbed, the cells may instead be pushed into the space between the epithelial layer and the organ. When this happens, the cells are more likely to survive and may then form a tumor that invades the organ. Gu et al. interfered with extrusion by reducing the levels of the S1P2 receptor in layers of human epithelial cells grown in the laboratory. Fewer epithelial cells were squeezed out of these cell layers, making the layers up to three times as thick in places. Moreover, mutant zebrafish lacking the S1P2 receptor also accumulated epithelial masses throughout their bodies. Gu et al. found that disrupting the extrusion process made the cells resistant to chemotherapy, and that certain hard-to-treat human pancreatic, lung, and colon cancers had lower levels of the S1P2 receptors. Boosting the activity of S1P2 receptors helped to restore normal extrusion and reduced the size of pancreatic tumors in mice. Gu et al. then focused on an enzyme called Focal Adhesion Kinase that helps cells to survive. Treating zebrafish with a drug to block the activity of this enzyme left normal fish unharmed. However, in mutant fish with malfunctioning extrusion pathways, the drug rescued the number of cells that died, reduced the size and number of masses, and cured their leaky skin barrier. If further studies confirm the results, the drug may offer a new, less toxic, treatment for certain cancers that do not respond to currently available treatments. DOI:
    eLife Sciences 01/2015; 4. DOI:10.7554/eLife.04069 · 8.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Both developing and adult organisms need efficient strategies for wound repair. In adult mammals, wounding triggers an inflammatory response that can exacerbate tissue injury and lead to scarring. In contrast, embryonic wounds heal quickly and with minimal inflammation, but how this is achieved remains incompletely understood. Using in vivo imaging in the developing brain of Xenopus laevis, we show that ATP release from damaged cells and subsequent activation of purinergic receptors induce long-range calcium waves in neural progenitor cells. Cytoskeletal reorganization and activation of the actomyosin contractile machinery in a Rho kinase-dependent manner then lead to rapid and pronounced apical-basal contractions of the neuroepithelium. These contractions drive the expulsion of damaged cells into the brain ventricle within seconds. Successful cell expulsion prevents the death of nearby cells and an exacerbation of the injury. Cell expulsion through neuroepithelial contraction represents a mechanism for rapid wound healing in the developing brain. Copyright © 2014 Elsevier Inc. All rights reserved.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms `intestinal barrier¿ and `intestinal permeability¿ are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by `intestinal permeability¿. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and ¿ more recently recognized ¿ obesity and metabolic diseases. All these diseases are characterized by inflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention.
    BMC Gastroenterology 11/2014; 14(1):189. DOI:10.1186/s12876-014-0189-7 · 2.11 Impact Factor