May 17, 2012

Hit the road, Jack! Cells undergo cell death all the time, but it’s important for a tissue to clear these cells out before problems crop up. Today’s image is from a paper showing the migration of apoptotic cells, and revealing the role a protein called elmo1 in cell corpse clearing.

Apoptosis is programmed cell death, and is as part of normal development and tissue function as cell division is. Apoptotic cells must be cleared out of the healthy tissue, and failure to do so can result in inflammation and autoimmunity. A recent paper describes the clearance of apoptotic cells in the developing brain of zebrafish, using real-time microscopy to track apoptotic cells. van Ham and colleagues found that apoptotic cells are able to migrate to the periphery of the tissue to contribute to their own removal, and use their own actin cytoskeleton to do so. Later in development, cell corpses are engulfed by large macrophage cells with the help of a protein called elmo1, a protein known to play a role in cell engulfment in other tissues. In the images above, a cell in the process of undergoing apoptosis migrates through the neural tube of a zebrafish embryo.

van Ham, T., Kokel, D., & Peterson, R. (2012). Apoptotic Cells Are Cleared by Directional Migration and elmo1- Dependent Macrophage Engulfment Current Biology, 22 (9), 830-836 DOI: 10.1016/j.cub.2012.03.027
Copyright ©2012 Elsevier Ltd. All rights reserved.

May 10, 2012

I’m an old fart…heck, I was born an old fart. So, you won’t be seeing me in da club. But if I ever go, I’ll be reassured knowing that bouncers kick the knuckleheads out and keep the crowd to a safe limit. Though they may be beefy tough guys, bouncers are clearly getting their cues from epithelial cells, which extrude both dying and healthy cells when overcrowded, according to a recent paper.

Cell extrusion is the process in which epithelial cells get rid of apoptotic, or dying, cells. By getting rid of dying cells, the epithelial sheet can maintain its tight barrier function for the tissue or organ. A recent paper shows that epithelial sheets can also extrude healthy, living cells. According to Eisenhoffer and colleagues, an epithelial sheet overcrowded with cells will extrude living cells in order to maintain tissue homeostasis. This mechanism was found in human, canine, and zebrafish epithelial cells, and could be induced by overcrowding epithelial cells in a stretched, then released, chamber in the lab. Cells are extruding in the images of human colon epithelial tissue above. A dying cell in the process of extruding (right) shows caspase-3 staining (green, arrow), a marker for apoptosis, while a living cell extruding (left, arrowhead) does not.

 

Eisenhoffer, G., Loftus, P., Yoshigi, M., Otsuna, H., Chien, C., Morcos, P., & Rosenblatt, J. (2012). Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia Nature, 484 (7395), 546-549 DOI: 10.1038/nature10999

Adapted by permission from Macmillan Publishers Ltd, copyright ©2012

 

March 5, 2012

Scenario: You’re at my house for a dinner and I make you a mind-blowing chocolate tart. You ask why it is so durn good, and I pass along the fact that Nutella is the ass-kicking ingredient. Next thing you know, you’re trying to add Nutella to everything at home….and by golly, it makes (many) things taste better. Today’s image is from a paper characterizing the relationship between the many cellular changes after treatment by antimitotic drugs. Knowing how these drugs work (by analogy, finding the ass-kicking “ingredient”) can help folks develop improved anti-cancer drugs.

Many anticancer drugs are antimitotic drugs, meaning they function by blocking the progress of cell division during mitosis. In addition to arresting mitosis, these drugs cause apoptosis, DNA damage, and induction of p53 (a tumor suppressor gene), and a recent paper investigates the relationship between all of these events. After treating cells with powerful antimitotic drugs, Orth and colleagues found that the resulting prolonged mitotic arrest (or slippage from that arrest) causes DNA damage, which in turn causes an induction of p53. The DNA damage was inhibited when these treated cells were prevented from launching the pathway for apoptosis, which is programmed cell death. So, Orth and colleagues concluded that the prolonged mitotic arrest caused by antimitotic drugs results in a partial activation of apoptosis. Understanding this partial apoptotic response in the context of treating tumors should help guide development of improved cancer therapies. The images above show increasing DNA damage (red spots) after prolonged treatment with an antimitotic drug, compared with an untreated cell (top left). By 16 and 48 hours of drug treatment (bottom), cells had very high levels of DNA damage. Arrows point to mitotic cells.

Orth, J., Loewer, A., Lahav, G., & Mitchison, T. (2011). Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction Molecular Biology of the Cell, 23 (4), 567-576 DOI: 10.1091/mbc.E11-09-0781

November 14, 2011

Just like Willy Wonka’s trained squirrels getting rid of the bad nuts, an epithelial sheet is able to push out a dying or unwanted cell, all while maintaining an intact barrier. Today’s image is from a paper describing how the direction of cell extrusion is regulated, and is from the same lab that provided a cell extrusion image featured earlier this year (check it out here).

When a cell is extruded from an epithelial sheet, it can be pushed either apically, into the lumen of the organ, or basally, further into the underlying tissue surrounding the organ. This direction is important—although most extruded cells are eliminated on the apical side, living cells that are extruded basally may affect development or become an invading cancerous cell. A recent paper describes results showing that the tumor suppressor protein APC can target microtubules to the cell base in order to drive apical extrusion. In addition, this function of APC is required in the cell that is being extruded, in turn controlling the direction of the actin contractions that squeeze the cell out of the epithelial sheet. Cells either without APC or with a mutated form of APC extruded on the basal side. In the images above, microtubules (green) in wild-type epithelial cells (left) are highly organized and oriented towards the cell being extruded (asterisk). In APC mutant epithelial cells (right), microtubules are reduced and disorganized around the extruding cell.

Marshall, T., Lloyd, I., Delalande, J., Nathke, I., & Rosenblatt, J. (2011). The tumor suppressor adenomatous polyposis coli controls the direction in which a cell extrudes from an epithelium Molecular Biology of the Cell, 22 (21), 3962-3970 DOI: 10.1091/mbc.E11-05-0469

October 27, 2011

Apoptosis sounds like a brutal death for a cell—all of that blebbing, fragmentation, and destruction just gives me the willies. Most of the time, cells only go through apoptosis when absolutely necessary thanks to proteins such as Bcl-x_L. A recent paper finds a new, non-apoptosis role for Bcl-x_L in cell health and survival.

The Bcl-2 family is made up of proteins that can either drive or inhibit apoptosis, which is programmed cell death. Bcl-x_L is a Bcl-2 family member that inhibits apoptosis by binding Bax, a pro-apoptosis family member, at the outer membrane of mitochondria. There, Bcl-x_L inhibits the release of cytochrome c, which during apoptosis serves to kick-start a cascade that destroys the cell. A recent paper finds an exciting new role for Bcl-x_L outside of apoptosis. Chen and colleagues found Bcl-x_L localized to the inner mitochondrial membrane, contrary to previous opinion that it is only found at the outer mitochondrial membrane. At the inner membrane, Bcl-x_L is important in maintaining the efficiency of the mitochondria by inhibiting excessive flux of ions across the inner membrane. The images above are electron micrographs of mitochondria. Antibodies that label Bcl-x_L are bound to tiny gold beads, which are found at the inner membrane (black arrows), as well as the outer membrane (arrowheads) and adjacent membranes (line arrows).

Chen, Y., Aon, M., Hsu, Y., Soane, L., Teng, X., McCaffery, J., Cheng, W., Qi, B., Li, H., Alavian, K., Dayhoff-Brannigan, M., Zou, S., Pineda, F., O'Rourke, B., Ko, Y., Pedersen, P., Kaczmarek, L., Jonas, E., & Hardwick, J. (2011). Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential originally published in The Journal of Cell Biology, 195 (2), 263-276 DOI: 10.1083/jcb.201108059

May 26, 2011

“Bring out yer dead!” Thankfully, epithelial sheets have a much more efficient and beautiful way of clearing out dying cells than the famous Monty Python scene. Today’s stunning images are from a paper describing the signaling epithelial cells use to push out dying cells. It’s no wonder that the authors’ image made the cover of Journal of Cell Biology!

The function and health of an organ strongly depends on the integrity of the epithelial sheet protecting it. In order to preserve the epithelial barrier, dying cells are pushed out of the epithelial sheet in a precise and finely-tuned process called apoptotic cell extrusion. In this event, cells surrounding the dying, apoptotic cell form an actin and myosin ring that contracts to push the dying cell out of the sheet. A recent paper describes the signaling that takes place to initiate cell extrusion. The dying cell produces a signal called bioactive lipid sphingosine-1-phosphate (S1P), which activates actin-myosin contraction via its receptor (S1P2) in neighboring cells. The images above show epithelial sheets in normal and S1P2 mutant zebrafish larvae. In the mutant, the apoptotic cell (green) stays in the epithelial sheet and lacks the actin ring (red) seen in the wild-type tissue.

Gu, Y., Forostyan, T., Sabbadini, R., & Rosenblatt, J. (2011). Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway originally published in The Journal of Cell Biology, 193 (4), 667-676 DOI: 10.1083/jcb.201010075

June 10, 2010

In the cell, there are many proteins that function in several different processes. Two of these proteins are caspase-8 and Rab5. Caspase-8 is primarily known for its role in promoting apoptosis (programmed cell death), while Rab5 is known for its involvement in endocytosis. A paper early this year reveals that Rab5 functions downstream of an activated caspase-8 signal to alter adhesion and migration of a cell. Images above show colocalization of Rab5 (red) and actin (blue) at membrane ruffles of migrating cells expressing caspase-8 (bottom), compared to control cells (top).

Reference: Vicente A. Torres, Ainhoa Mielgo, Simone Barbero, Ruth Hsiao, John A. Wilkins, and Dwayne G. Stupack. Authors’ Molecular Biology of the Cell paper can be found here.