Stem cell research has made leaps and bounds the past few years, and it’s no wonder why…they hold amazing therapeutic potential and teach us so much about development. A recent paper makes another leap for the stem cell community and shows some amazing things that stem cells can do.
Stem cells have the ability to differentiate into many cell types, and this ability requires that stem cells respond to different cues depending on the resulting cell type. Biologists have been able to induce differentiation of stem cells into various cell types in culture, and recently a group of researchers have induced differentiation of stem cells into a three-dimensional tissue. Spence and colleagues applied a sequence of growth factors to cultured stem cells to mimic those seen during intestinal development. After several days, these cells differentiated into three-dimensional intestinal tissue. As seen in the images above, these “organoids” were columnar-shaped and very similar to actual intestinal tissue. Images on left show the stem cells earlier in the experiment, while images on right show the organoids several days later.
Spence, J., Mayhew, C., Rankin, S., Kuhar, M., Vallance, J., Tolle, K., Hoskins, E., Kalinichenko, V., Wells, S., Zorn, A., Shroyer, N., & Wells, J. (2010). Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro Nature, 470 (7332), 105-109 DOI: 10.1038/nature09691
Adapted by permission from Macmillan Publishers Ltd, copyright 2011
We all need balance in our lives to be happy and healthy, and the little embryo versions of ourselves were no different. When our brain and nervous system developed, our neural precursor cells made sure there was a balance between proliferation and differentiation. A recent paper adds to our understanding of how this happens.
The development of our nervous system is a process that relies on a delicate balance of growth and differentiation. Our neural precursor cells are progenitor cells that can either proliferate as more precursors or differentiate into neurons. Notch1 is a signaling receptor that is known to inhibit the differentiation route and promote proliferation of more precursors. A recent paper identified Prox1 as a transcriptional repressor that allows differentiation of neurons by suppressing the expression of the Notch1 gene. Image above shows neural precursor cells grown in culture as neurospheres from chick spinal cords. When growth factors are added to the culture, the precursors maintain the ability for proliferation and self-renewal, as seen as the high number of undifferentiated cells (red) and low number of Prox1-positive cells (green). The nuclei of cells are in blue.
Kaltezioti, V., Kouroupi, G., Oikonomaki, M., Mantouvalou, E., Stergiopoulos, A., Charonis, A., Rohrer, H., Matsas, R., & Politis, P. (2010). Prox1 Regulates the Notch1-Mediated Inhibition of Neurogenesis PLoS Biology, 8 (12) DOI: 10.1371/journal.pbio.1000565
Cancer cells have taught biologists about a lot of wacky things that can happen when things don’t go merrily along for a cell. Entosis is a process in which a living cell is internalized into a neighboring cell, and has been found to occur in some tumors. A recent paper describes exactly what can go wrong here.
Aneuploidy refers to a cell having an incorrect number of chromosomes, and is a feature of many cancers. Typically, aneuploidy occurs from a failure in cytokinesis, the physical division of a cell after mitosis, due to misregulation or mutation of genes involved in cell division. Sometimes, however, aneuploidy can occur from a non-genetic failure of cytokinesis, according to a recent paper. In this paper, Krajcovic and colleagues look at cytokinesis failures due to entosis, a process in which living cells are internalized by their neighboring cells. These cell-in-cell structures are found in some tumors, and the outer “host” cell is frequently aneuploid. This aneuploidy occurs when the internalized cell physically disrupts the constriction required to cleave two cells during cytokinesis, as seen in the images above. Cytokinesis of the cell-in-cell structure (left) is not going well compared with a normal cell (right). Red labels (and in black and white insets) mark active constriction during cytokinesis, and should be symmetric around the cells. The mitotic spindle is labeled in green, and chromosomes in blue.
BONUS!! Movie of above cell, attempting cytokinesis, can be found here. More cool movies from this paper can be found here.
Krajcovic, M., Johnson, N., Sun, Q., Normand, G., Hoover, N., Yao, E., Richardson, A., King, R., Cibas, E., Schnitt, S., Brugge, J., & Overholtzer, M. (2011). A non-genetic route to aneuploidy in human cancers Nature Cell Biology, 13 (3), 324-330 DOI: 10.1038/ncb2174
Adapted by permission from Macmillan Publishers Ltd, copyright 2011
How do cells organize themselves into vastly different tissues and organs during development? This is a fundamental question for developmental biologists, and thankfully amazing microscopy can let us see it all unfold (or fold, or zip, or contract, or converge, or invaginate, or…well, you get the point).
Morphogenesis is the physical shaping of an organism during development. Because of the dynamic nature of morphogenesis, it has been helpful for biologists to image these events while they are happening, rather than taking single snapshot images. A recent paper uses live imaging microscopy techniques to look at the fruit fly’s egg chamber, which elongates 1.7-fold during its development. This paper describes how the surface of the egg undergoes oscillations of contractions that are due to oscillations of myosin accumulation. These contractions lead to the elongation of the tissue. Image above shows the periodic pattern of myosin accumulation (red) at different developmental stages of egg chamber development, with cartoons (top) as a guide.
BONUS!! Movie of above image can be seen here. Many more movies from this paper can be found here.
He, L., Wang, X., Tang, H., & Montell, D. (2010). Tissue elongation requires oscillating contractions of a basal actomyosin network Nature Cell Biology, 12 (12), 1133-1142 DOI: 10.1038/ncb2124
Adapted by permission from Macmillan Publishers Ltd, copyright 2011
One of the first jobs an embryo must complete is to orient the body’s head/tail axis. It seems simple enough, but for an early embryo with not many cells, it is an amazing task. A recent paper describes the use of amazing microscopy to visualize this process in a mouse embryo.
The anterior visceral endoderm (AVE) is a subset of cells from the visceral endoderm that sets up the anterior-posterior (head-tail) body axis by migrating to the future anterior region. A recent paper precisely describes AVE migration and the relationship between the AVE and its neighbors. In this paper, Trichas and colleagues show that the AVE cell move by exchanging neighbors, or intercalate, within an unbroken epithelial sheet. In addition, AVE migration is regulated by different localization patterns of actin and certain signaling pathways. Images above are 3D reconstructions of mouse embryo images, with AVE cells labeled green and two different epithelial junction proteins are labeled in magenta (ZO-1 is top, E-cadherin is bottom). Before (left), during (middle), and after (right) migration, the epithelial sheet remains intact due to the cell intercalation of the AVE.
BONUS!! Below is a movie of how 3D renderings compare with the raw images that are acquired on the microscope. For many more awesome movies, check out the link here.
Trichas, G., Joyce, B., Crompton, L., Wilkins, V., Clements, M., Tada, M., Rodriguez, T., & Srinivas, S. (2011). Nodal Dependent Differential Localisation of Dishevelled-2 Demarcates Regions of Differing Cell Behaviour in the Visceral Endoderm PLoS Biology, 9 (2) DOI: 10.1371/journal.pbio.1001019
Actin is as essential to a cell’s function as Girl Scout cookies are to mine. With all of the biologists sorting out the many different functions and regulators of actin, it’s easy to get a little overwhelmed as a reader and actin admirer. Thankfully, a recent paper delves into the world of RhoA to clarify exactly what it is doing in our skin cells.
RhoA is an actin small GTPase, which means it serves as a molecular switch to regulate actin cytoskeleton organization. RhoA is important in many processes including cytokinesis, cell-cell junctions, and stress fiber formation. Previous research led to the thought that RhoA was crucial for skin development and function, but a recent paper finds otherwise. In this paper, Jackson and colleagues generated mice with RhoA absent from keratinocytes, which are the outer-most cells of our skin. The skin of these mice developed similar to control mice, yet the loss of RhoA in keratinocytes did lead to problems in cytokinesis and cell migration and spreading. Images above show normal (left) and RhoA mutant (right) epidermis tissue with labels for different keratinocyte proteins (red), the cell adhesion receptor α6 integrin (green), and DNA (blue). Both normal and RhoA mutants show normal skin development.
Jackson, B., Peyrollier, K., Pedersen, E., Basse, A., Karlsson, R., Wang, Z., Lefever, T., Ochsenbein, A., Schmidt, G., Aktories, K., Stanley, A., Quondamatteo, F., Ladwein, M., Rottner, K., van Hengel, J., & Brakebusch, C. (2011). RhoA is dispensable for skin development, but crucial for contraction and directed migration of keratinocytes Molecular Biology of the Cell, 22 (5), 593-605 DOI: 10.1091/mbc.E09-10-0859
Think of the first time you kissed your partner…I’m sure it led to piloerection. Nerds, stop the giggling…I’m talking about goosebumps! The stunning image above is from a paper describing the relationship between hair follicles and the muscles that cause goosebumps.
We have epidermal stem cells in our hair follicles in a region called the bulge. The cells in the bulge are closely associated with the arrector pili muscle (APM), which is the muscle responsible for causing goosebumps. A recent study describes how bulge cells deposit a protein called nephronectin into the underlying basement membrane, and this provides a niche for APM differentiation during hair follicle development. Image above shows hair follicles (blue) and smooth muscle proteins found in the APM (red, green). The white brackets show groups of hair follicles that share APMs.
Fujiwara, H., Ferreira, M., Donati, G., Marciano, D., Linton, J., Sato, Y., Hartner, A., Sekiguchi, K., Reichardt, L., & Watt, F. (2011). The Basement Membrane of Hair Follicle Stem Cells Is a Muscle Cell Niche Cell, 144 (4), 577-589 DOI: 10.1016/j.cell.2011.01.014
Copyright ©2011 Elsevier Ltd. All rights reserved.
Look all the way down to your toes and you’ll appreciate the feat (pun absolutely intended!) that your neurons accomplish in relaying signals over long distances to your brain. A recent paper discusses the interactions between the first sets of motor and sensory axons that find their way into limbs during development.
During development, motor and sensory axons align together as they project into a developing limb. A group recently showed how motor and sensory axons are mutually dependent on one another for their correct trajectories into a developing limb, and identified an important role for a protein called Neuropilin-1 in these interactions. Image above from the cover of PLoS Biology shows sensory (red) and motor (green) axons in the brachial plexus, a region where motor and sensory axons converge before being sorted into bundles. This tight bundling of the axons is affected in mice that lack Neuropilin-1 in either type of axon.
Huettl, R., Soellner, H., Bianchi, E., Novitch, B., & Huber, A. (2011). Npn-1 Contributes to Axon-Axon Interactions That Differentially Control Sensory and Motor Innervation of the Limb PLoS Biology, 9 (2) DOI: 10.1371/journal.pbio.1001020
Cover of PLoS Biology can be found here.
When I first learned about the elegant experiments of the late Ray Rappaport, I remember feeling like I was having a Zen moment. Amazing things can be learned from some of the simplest experimental designs, and this is a very calming and satisfying concept. Today’s image is from a paper using those same sea urchin eggs that Rappaport used*, and provides us with a great prediction tool for determining how a cell will divide.
Many cells in an embryo must divide in a certain orientation, and many biologists have tried to make predictions on how this orientation is determined. Add the varying shapes a cell may take on within a developing organism, and making these predictions is less than straightforward. In order to make predictions on cell division orientation, a group of biologists set sea urchin eggs into wells of varying shapes. By monitoring the cell division axis in many cells set in wells of many shapes, Minc and colleagues developed a computational model that predicts how the cell division axis is determined for any given shape. Images above show sea urchin embryos in wells of different shapes.
Minc, N., Burgess, D., & Chang, F. (2011). Influence of Cell Geometry on Division-Plane Positioning Cell, 144 (3), 414-426 DOI: 10.1016/j.cell.2011.01.016
©2011 Elsevier Ltd. All rights reserved.
* Correction: Rappaport didn't use sea urchin eggs. In most of his experiments, he used a different echinoderm--the sand dollar. Thanks to Bob G. for the note!
