August 29, 2014

Stem cells in adults are responsible for tissue renewal and many cancers. So, the hunt for stem cells is important and has already been successful, with stem cell populations identified in countless types of tissues. Stem cells in the ovary, however, were shy to show themselves until a recent study using a marker for the Wnt protein Lgr5.

In adults, stem cells are responsible for maintaining homeostasis during normal wear and tear of a tissue. The ovary and its ovary surface epithelium (OSE) experience remodeling during adulthood, yet stem cells of the ovary have been hard to find. A recent paper by Ng and colleagues describes the identification of stem cells in the ovary using markers for the Wnt target protein Lgr5. Lgr5 marks stem cells in several epithelial tissues. Ng and colleagues identified Lgr5+ cells in the mouse ovary starting from ovary organogenesis and lasting into adulthood. Using lineage tracing, Ng and colleagues confirmed that Lgr5+ cells are, in fact, stem cells that contribute to development, homeostasis, and repair of the OSE and associated structures. In the images above, Lgr5+ cells (green) are visible in embryonic (left) and postnatal (middle, right) ovarian tissue.

Ng, A., Tan, S., Singh, G., Rizk, P., Swathi, Y., Tan, T., Huang, R., Leushacke, M., & Barker, N. (2014). Lgr5 marks stem/progenitor cells in ovary and tubal epithelia Nature Cell Biology, 16 (8), 745-757 DOI: 10.1038/ncb3000
Adapted by permission from Macmillan Publishers Ltd, copyright ©2014

June 19, 2014

As the widespread therapeutic use of stem cells moves closer to reality, I just fasten my seatbelt a little tighter. An exciting time for stem cells and their scientist stalkers, a recent paper shows the regeneration of damaged monkey hearts by human embryonic stem cell-derived cardiomyocytes.
 
Human embryonic stem cells (hESCs) can be programmed to differentiate into countless different cell types. hESCs are already being tested in humans to treat retinal diseases and spinal cord injuries. hESCs can be differentiated into cardiomyocytes, or heart muscle cells, to potentially repair a damaged heart after injury or failure. In a recent study, Chong and colleagues used hESC-derived cardiomyocytes (hESC-CMs) to repair injured monkey hearts, which are more comparable to human hearts in size and number of cardiomyocytes required. After first developing techniques for producing large, clinical-scale cryopreserved batches of hESC-CMs, Chong and colleagues found that these cells successfully re-muscularized the injured monkey hearts. The electromechanical coupling between host heart tissue and hESC-CM graft tissue was successful, yet non-fatal arrhythmias were observed. In the images above, host vessels (red) extend into graft tissue (white, boxed region and higher magnification below) and are able to successfully perfuse the graft tissue.

Chong, J., Yang, X., Don, C., Minami, E., Liu, Y., Weyers, J., Mahoney, W., Van Biber, B., Cook, S., Palpant, N., Gantz, J., Fugate, J., Muskheli, V., Gough, G., Vogel, K., Astley, C., Hotchkiss, C., Baldessari, A., Pabon, L., Reinecke, H., Gill, E., Nelson, V., Kiem, H., Laflamme, M., & Murry, C. (2014). Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts Nature, 510 (7504), 273-277 DOI: 10.1038/nature13233
Adapted by permission from Macmillan Publishers Ltd, copyright ©2014

March 12, 2014

I love a lot of things that are rings, especially donuts. Turns out, though, that ring chromosomes are terrible news. A recent paper shows the loss of ring chromosomes when cells are reprogrammed, suggesting possible ‘chromosome therapy’ through cell reprogramming.

Ring chromosomes form when the two arms of a chromosome fuse, and are sometimes associated with large terminal deletions. These ring chromosomes lead to birth defects, mental disabilities, and growth retardation. Unfortunately, there are no treatments for ring chromosome disorders due the severity of the aberrations. In a recent study, Bershteyn and colleagues generated induced pluripotent stem cells (iPSCs) from cells of a Miller Dieker Syndrome patient with large deletions on ring chromosome 17. The induced stem cells lost the ring chromosome and duplicated the normal homologous chromosome through a mechanism called compensatory uniparental disomy. The images above show two karyotypes—one with the ring chromosome 17 (left, inset), and one without (right).

Bershteyn, M., Hayashi, Y., Desachy, G., Hsiao, E., Sami, S., Tsang, K., Weiss, L., Kriegstein, A., Yamanaka, S., & Wynshaw-Boris, A. (2014). Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells Nature, 507 (7490), 99-103 DOI: 10.1038/nature12923
Adapted by permission from Macmillan Publishers Ltd, copyright ©2014

Febrary 26, 2014

Not all stem cells are created equally. Some are totipotent, meaning they can divide and differentiate into any cell type, while some are unipotent, meaning they can differentiate into one specific cell type. Understanding the potenty of various stem cells is an important step towards understanding how tissues are developed, remodeled, and maintained. Today’s beautiful images are from a study of stem cells in the mammary gland.

Mammary glands go through a lot of changes during both puberty and adulthood, and are made up of two main cell lineages—myoepithelial and luminal. The function of mammary stem cells was previously unclear—in one model, bipotent stem cells contribute to the development and maintenance of adult mammary glands, while in the other model, those stem cells are unipotent and separately control mammary gland lineages. A recent cell fate mapping study by Rios and colleagues featured the use of multicolor reporters and 3D imaging. Rios and colleagues found that mammary stem cells are indeed bipotent, and function in ductal remodeling and homeostasis in the adult mammary gland. In the image above, the sea of colorful cells seen in the mid-puberty mouse mammary gland (top) indicates the presence of multiple progenitors. The arrow and arrowhead in the inset image point to myoepithelial and luminal cells, respectively. As puberty progressed (bottom), discreet regions of similarly-colored cells indicate clonal expansion and a shift towards adulthood.

Rios, A., Fu, N., Lindeman, G., & Visvader, J. (2014). In situ identification of bipotent stem cells in the mammary gland Nature, 506 (7488), 322-327 DOI: 10.1038/nature12948
Adapted by permission from Macmillan Publishers Ltd, copyright ©2014

September 18, 2012

It’s hard to not get excited about stem cells and their potential. The advances that will likely take place due to stem cells (and already have!) couldn’t have been dreamed up by even George Jetson’s creators. (Side note: where’s my flying car and robot housekeeper?!) Today’s image is from a paper showing the success of stem cells in healing a spinal cord injury.

Stem cells are unspecialized cells able to differentiate into various other cell types throughout development and adulthood. The prospect of using stem cells in treating diseases or repairing traumatic injuries drives the research of many biologists. A recent paper describes how stem cells can repair a spinal cord injury in mice. Lu and colleagues grafted mouse neural stem cells onto the sites of severe spinal cord injuries, and found that these cells differentiated into different cell types, including neurons. These neurons projected long axons that were able to form synapses with host neurons, and allowed functional recovery of the spinal cord. Human stem cells exhibited similar growth within the injured spinal cords of mice. The images above show the site of an injured spinal cord, several weeks after the injury. Neural stem cells (green) were able to grow and completely fill in the injured area.

Copyright ©2012 Elsevier Ltd. All rights reserved.
Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, Brock J, Blesch A, Rosenzweig ES, Havton LA, Zheng B, Conner JM, Marsala M, & Tuszynski MH (2012). Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell, 150 (6), 1264-73 PMID: 22980985

August 2, 2012

 Sometimes you watch a movie, and then you watch it again. And again. And again. Maybe it was Goonies, back when you were a kid (or adult)…or it was a pair of otters holding hands or a baby panda sneezing. Or maaaaybe it was watching stem cells and their progeny divide in real time, within the actual organism. Thanks to the technical gymnastics of a group of stem cell researchers, we can now see how stem cells and their progeny within a hair follicle divide and regenerate hair.

Tissue regeneration begins with stem cells and their immediate progeny. Knowledge of this process has been incomplete due to the difficulty of tracking all of the cell behaviors in living tissue. A group recently used high resolution imaging to track hair regeneration within hair follicles of mice over a long period of time. By tracking cell behaviors, Rompolas and colleagues found that the immediate progeny of stem cells actively divide to regenerate the tissue, while stem cells divide more slowly to contribute to hair regeneration over time. The stem cell progeny cell divisions are mostly aligned with the long axis of the hair. Finally, Rompolas and colleagues used cell ablation to show that a mesenchymal group of cells called the dermal papilla is required for hair regeneration. In the images above, stem cell progeny divisions can be seen in a live hair follicle undergoing growth. Three different cells are colored to show their divisions (right columns).

BONUS! Check out a movie of stem cell progeny divisions here and here, and a movie of stem cell divisions here. For all movies from this paper, click here.

Panteleimon Rompolas, Elizabeth R. Deschene, Giovanni Zito, David G. Gonzalez, Ichiko Saotome, Ann M. Haberman, & Valentina Greco (2012). Live imaging of stem cell and progeny behaviour in physiological hair-follicle regeneration Nature, 487 (7408), 496-499 DOI: 10.1038/nature11218
Adapted by permission from Macmillan Publishers Ltd, copyright ©2012

 

April 16, 2012

I’m a homebody. I admit it. We’re all supposed to be adventurous, live on the edge, blah blah blah….but I thrive at home with my family around me. Maybe this makes me more like a stem cell than you glamorous jet-setters out there, and that seems pretty okay to me. Stem cells must stay in their niche, and a recent paper shows how some stem cells in the fruit fly do this through regulation of asymmetric division.

When adult stem cells divide, they produce a daughter cell that will take on a specific cell fate and another stem cell. To maintain this stem cell identity a stem cell must stay within its niche, or its microenvironment. In the fruit fly testes, germline stem cells (GSCs) stay adjacent to the “hub” within their niche and divide asymmetrically. In these divisions, a centrosome is positioned near the hub-GSC interface, and this aligns the mitotic spindle perpendicular to the hub. After cell division, the daughter cell that will remain a stem cell maintains its hub-GSC interface, while the differentiating cell is positioned further away. A recent paper shows that poor nutrient conditions prevent proper centrosome positioning in GSCs, which causes a delay in cell division via the centrosome orientation checkpoint. Roth and colleagues show that centrosome orientation is regulated by the insulin receptor pathway through its effect on the localization of Apc2, a cortical anchor for GSC centrosomes. The image above shows GSCs surrounding the hub (star) in a fruit fly testes cultured in poor nutrient conditions. One cell has correct centrosome orientation (yellow circle, centrosomes are red dots), while two cells (white circle) have misoriented centrosomes (arrowheads).

BONUS! Aren't GSCs pretty!? Check out these other posts on GSCs (here and here) that I wrote last week.

Roth, T., Chiang, C., Inaba, M., Yuan, H., Salzmann, V., Roth, C., & Yamashita, Y. (2012). Centrosome misorientation mediates slowing of the cell cycle under limited nutrient conditions in Drosophila male germline stem cells Molecular Biology of the Cell, 23 (8), 1524-1532 DOI: 10.1091/mbc.E11-12-0999

November 28, 2011

Asymmetric cell division results in two unequal daughter cells and without it, stem cells would not hold the attention of biologists, sick patients, politicians, and those loud nut-jobs who have more passion than knowledge. Check out today’s image, from a paper identifying a new protein complex important in asymmetric division.

Asymmetric division occurs throughout development, and is when a cell divides to result in two daughter cells that are unequal in size and/or cell fate. Part of this process is the establishment of the axis along which the cell will divide. Once this polarity is established, the mitotic spindle can line up accordingly. Fruit fly neural stem cells, called neuroblasts, divide asymmetrically to result in the birth of another neuroblast and a smaller ganglion mother cell, which eventually gives rise to neurons. A recent paper identifies a new role for a signaling complex in establishing neuroblast polarity. In this paper, Carmena and colleagues found that the Rap1–Rgl–Ral complex of proteins regulates polarity establishment in fruit fly neuroblasts, and works alongside other well-studied polarity proteins such as aPKC, Par6, and Pins. As seen in the images above, Rap1 (bottom row, green in merged; arrows) is enriched on only one side (apical side) of neuroblasts throughout division (DNA is in red).

Carmena, A., Makarova, A., & Speicher, S. (2011). The Rap1-Rgl-Ral signaling network regulates neuroblast cortical polarity and spindle orientation originally published in The Journal of Cell Biology, 195 (4), 553-562 DOI: 10.1083/jcb.201108112

October 13, 2011

I started on my biology journey with my Ranger Rick subscription as a tiny kid (quickly followed by my Fisher-Price microscope). I loved wildlife, and felt heartbreak for declining populations of so many species. Now that I’m trying to pass along this conservation concern and love of animals to my F1, I’m excited to talk about how stem cells may help save the animals!

Some species have too few individuals to allow successful breeding and genetic diversity. For example, the drill is an endangered primate of Africa and the northern white rhinoceros is a critically endangered species with only 7 known individuals (that’s right…not 7 million or 7 thousand, just 7). A recent method paper describes the generation of induced pluripotent stem cells (iPSCs) from both of these endangered species. Ben-Nun and colleagues generated fully reprogrammed iPSC lines from cryopreserved fibroblasts. These cell lines had characteristics of pluripotent cells in other species (ie, alkaline phosphatase activity, Oct4, Sox2, and Nanog). Images above show differentiated embryoid bodies developed from the northern white rhinoceros’ iPSCs. These differentiated cells have markers for all three developmental germ layers, as indicated at the bottom of the image (SMA = smooth muscle actin). Future applications of these iPSCs are truly exciting. In addition to therapeutic uses for sick captive animals, iPSC-derived germ cells can help increase species numbers and diversity (in combination with assisted reproduction).

Friedrich Ben-Nun, I., Montague, S., Houck, M., Tran, H., Garitaonandia, I., Leonardo, T., Wang, Y., Charter, S., Laurent, L., Ryder, O., & Loring, J. (2011). Induced pluripotent stem cells from highly endangered species Nature Methods, 8 (10), 829-831 DOI: 10.1038/nmeth.1706
Adapted by permission from Macmillan Publishers Ltd, copyright ©2011

May 23, 2011

“Hooolllly crap, this is so cool!” was what I said to my (accountant) husband after I read this paper. I did an interpretive dance to describe the many cool things in this particular paper, and I know you will too. Today’s image is from a recent paper about understanding the cellular mechanisms that underlie the very complicated mental disorder schizophrenia.

Schizophrenia is a mental disorder characterized by disorganized thought processes and emotional dysfunction. There is a strong genetic component to the disorder, yet the basic cellular mechanisms that occur in schizophrenic patients is not completely understood. Past studies have looked at post-mortem brains, which have taught biologists a lot about what a schizophrenic’s brain looks like. These studies, however, cannot help pinpoint the specific cells affected by schizophrenia and the molecular mechanisms that lead to the disorder. A recent paper does amazing acrobatics to figure out these unknowns. In this paper, Brennand and colleagues took fibroblasts from schizophrenia patients who have a high likelihood of having a genetic component to their disorder. These fibroblasts were reprogrammed into pluripotent stem cells, and then differentiated into neural progenitor cells and neurons. These neurons had decreased connectivity, diminished numbers of neurites, and altered levels of many key neuronal proteins and signals (glutamate receptors, for example…a biggie for neurons). Images above show the difference in neuronal connectivity in the neurons induced from stem cells in healthy (left) and schizophrenic (right) patients.

Brennand, K., Simone, A., Jou, J., Gelboin-Burkhart, C., Tran, N., Sangar, S., Li, Y., Mu, Y., Chen, G., Yu, D., McCarthy, S., Sebat, J., & Gage, F. (2011). Modelling schizophrenia using human induced pluripotent stem cells Nature, 473 (7346), 221-225 DOI: 10.1038/nature09915

Adapted by permission from Macmillan Publishers Ltd, copyright 2011

March 31, 2011

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

March 10, 2011

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.

January 3, 2011

Cancer is a loaded word for many biologists—it is made up of thousands of different diseases when you realize how many different paths can be taken in order for cells to lead to cancer. There are so many biologists investigating cancer, and sometimes there are discoveries that shake up our understanding. These shake-ups are key to making the big steps towards a cure that patients, survivors, and victims all hope for.

Cancer progression involves growth of a tumor as well as metastatic spread of cancerous cells to other tissues. Tumor growth requires the development of a blood supply for the tumor, and it was previously known that outside blood vessels get induced to sprout new vessels at the site of the tumor. A recent set of papers in Nature describe the ability of tumor stem cells in glioblastoma cancer to induce production of endothelial cells used in vessel formation. Images above show endothelial glioblastoma cells forming tubular vascular networks, a key step towards vessel formation, in a three-dimensional culture. DAPI shows nuclei of cells (blue), CD105 indicates dividing angiogenic endothelial cells (green), and DiI-AcLDL labels vascular endothelial cells (red). Image on right shows phase contrast of the tubular network.

Adapted by permission from Macmillan Publishers Ltd, copyright 2010.

Wang, R., Chadalavada, K., Wilshire, J., Kowalik, U., Hovinga, K., Geber, A., Fligelman, B., Leversha, M., Brennan, C., & Tabar, V. (2010). Glioblastoma stem-like cells give rise to tumour endothelium Nature, 468 (7325), 829-833 DOI: 10.1038/nature09624

Accompanying paper:
Ricci-Vitiani, L., Pallini, R., Biffoni, M., Todaro, M., Invernici, G., Cenci, T., Maira, G., Parati, E., Stassi, G., Larocca, L., & De Maria, R. (2010). Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells Nature, 468 (7325), 824-828 DOI: 10.1038/nature09557

Fantastic News and Views paper on these results:
Bautch, V. (2010). Cancer: Tumour stem cells switch sides Nature, 468 (7325), 770-771 DOI: 10.1038/468770a

June 17, 2010

Mesenchymal stem cells originate in the bone marrow, and are capable of differentiating into bone, cartilage, or fat cells depending on a variety of factors. A recent paper has found that cell shape plays a role in how these stem cells differentiate. When the mesenchymal stem cells are grown in shapes corresponding to higher contractility of the actin cytoskeleton, they are more likely to differentiate into bone cells, while cells in shapes of lower contractility are more likely to become fat cells. Image above shows cells grown in flower (top) or star (shapes). Cells on the left are stained for actin (green), focal adhesion protein vinculin (red), and DNA (blue); cells in the middle are stained for myosin. The heat maps on the right show high contractility in the star shaped cells, at the concave regions between the points of the star shape.

Reference: Kristopher A. Kilian, Branimir Bugarija, Bruce T. Lahn, and Milan Mrksich. Proc Natl Acad Science, 2010. 107(11): 4872–4877. doi: 10.1073/pnas.0903269107. Authors’ PNAS paper can be found here.