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Beyond the Embryo
By Thomas Deerinck, NCMIR, UCSD
Even after development stops, tissues still need regular maintenance. This is the job of "adult stem cells." These cells sit quietly in the nooks and crannies of organs, waiting for the signal to start dividing and differentiating.
Image: Mouse intestine section imagined with wide-field multi-photon microscopy. Actin (green) and lamin (red) are immunolabeled with quantum dots (QD 525 and QD 655, respectively); nuclei are shown in blue.
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Intestinal Stem Cells
By Paul Appleton, University of Dundee
The epithelium of the small intestine is the fastest self-renewing tissue in mammals. At the bottom of each villus is a narrow tubular structure, called the crypt (orange), where multi-potent stem cells reside. These cells divide daily, sending progeny up the crypt and the villus to replace the cells continuously sloughed away by passing food.
Image: 3D rendering of crypts in a mouse small intestine. The crypt lumen (orange) are surrounded by epithelial cells (blue). Image acquired with a Biorad Radiance 2100MP multi-photon microscope based on Nikon Eclipse TE2000-U inverted microscope. Multi-photon excitation provided by a Coherent Chameleon Titanium Sapphire laser at 790nm. Nuclei are stained blue with DAPI, and F-actin is stained orange with rhodamine phalloidin.
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Battling Baldness
By the Valentina Greco Laboratory, Yale School of Medicine
The human scalp sheds ~50–100 hairs each day. So what keeps you from balding? Stem cells, of course. At the base of a hair follicle, a population of stem cells wraps around the follicle, creating a compartment, called the "bulge." Like intestinal stem cells, these bulge stem cells have high proliferative capacity and are multipotent. In transplants, these cells can regenerate not only lost hair but also sebaceous glands and epidermis, too.
Image: Here, individual murine tail hair follicles are imaged with a Zeiss LSM510 confocal microscope. Stem cells are labeled green by the retention of H2BGFP, and all cells are stained red with the membrane dye FM464. This frame comes from a 3D reconstruction of a ~120 micron z stack obtained with a 20x objective (Zeiss Software).
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Hair Highlights
By Elizabeth Deschene, Valentina Greco Laboratory, Yale School of Medicine
Mammalian hair continuously cycles between a phase of active growth ("anagen") and one of quiescence ("telogen"). During the growth phase, the bulge stem cells (red) are rapidly dividing and adding to the hair's growth (~1 cm each month in humans). Then the follicle transitions into quiescent phase, when the stem cells stop dividing and growth ceases.
Images: Left: Immunofluorescent image of a murine hair follicle in the growth phase. Epithelial cells express histone H2B fused to GFP, labeling them green. Actively proliferating cells are labeled red with an antibody against the proliferation protein, Ki67; DAPI stains nuclei blue.
Right: Immunoflourescent image of a murine hair follicle in the quiescent phase. Epithelial cells (green) express the H2B-GFP fusion. This tissue section highlights two compartments: epithelial stem cells within the bulge (labeled red with an antibody against the transmembrane protein CD34) and stem cells' progenies within the hair germ (labeled blue with an antibody for P-Cadherin, a cell adhesion molecule).
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Not Born this Way
By Thomas Deerinck, NCMIR, UCSD
For decades researchers thought that the production of neurons stopped early in life, leaving the adult brain with a finite number of neurons. The discovery of neural stem cells with self-renewing capacity and multi-potency has radically changed this view, and it is now well accepted that the birth of new neurons continues throughout adulthood. Adult neurogenesis occurs in two primary locations: the olfactory bulb and the central part of the hippocampus, called the dendate gyrus (shown at the left).
Image: Widefield multi-photon fluorescence image of a rat hippocampus stained to reveal the distribution of glia (cyan), neurofilaments (green) and cell nuclei (yellow).
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Neural Stem Cells
By Ann-Shyn Chiang and Grigori Enikolopov, National Tsing Hua University, Taiwan and Cold Spring Harbor Laboratory
In the hippocampus, neural stem cells (green) sit in a layer below their progeny, the granule neurons (red). When activated by extrinsic stimuli, they enter mitosis and generate neuron progenitor cells, which eventually mature into neurons and migrate into the layer above. The number of neural stem cells in the hippocampus decreases over time, possibly contributing to the cognitive impairment associated with aging. One hypothesis is that, after a rapid series of divisions, these neural stem cells disappear via their conversion into astrocytes.
Image: Section of a mouse hippocampus imaged with Zeiss LSM 50 confocal microscope with a 40X C-Apochromat water-immersion objective lens (N.A. value 1.2, working distance 220 microns) at 62x magnification. Brain slices were fixed in 4% paraformaldehyde, immunolabeled, and then cleared in FocusClear (CelExplorer, Taiwan).
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Neuron Pipeline
By Yvonne Nolan, Louise Collins, Suzanne Crotty, University College Cork, Ireland
When cultured with growth factors in vitro, neural stem cells can generate neurons (red), as well as the cells that support them— astrocytes (green) and oligodendrocytes. In culture, neural stem cells group together in ball-like clusters, called neurospheres (bottom left). Neurospheres are of great therapeutic interest because they have the potential to regenerate and replace neurons lost in traumatic brain injury and neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis.
Image: This neurosphere (bottom left) was prepared from neural stem cells extracted from an embryonic rat midbrain. After allowing the cells to proliferate and expand for 7 days, they were imaged with confocal microscopy. Cells differentiated to neurons are labeled red with an antibody to βIII-tubulin, whereas astrocytes are labeled green with an antibody to glial fibrillary acidic protein (GFAP), an intermediate filament specific to astrocytes. All nuclei are stained blue with bisbenzamide.
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Body Regeneration
By Daniel Wagner, Whitehead Institute for Biomedical Research, MIT
The tiny freshwater worm, planarian (blue), is famous for its ability to regenerate its entire body even when it's chopped into a fragment ~1/300th its original size. This regenerative feat requires a special population of adult stem cells, called neoblasts (red), which can replace every cell type in the animal. Recently, Wagner et al. (2011) show that a single transplanted neoblast can regenerate an entire animal, demonstrating that neoblasts are indeed pluripotent stem cells that persist into adulthood.
Image: Here the head region from an adult planarian is imaged with a confocal microscope (Zeiss LSM 700). A growing colony of dividing cells that initiated from a single neoblast is labeled red by in situ hybridization with smedwi-1 mRNA. Hoechst stains the nuclei blue.
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Neuroscience Blossoms
By Yichen Shi and Rick Livesey, Gurdon Institute, University of Cambridge
The development of human iPSCs has opened a whole new continent for exploration, thanks largely to their remarkable ability to generate an unlimited source of any human cell type. For starters, now researchers can study the development and function of live human neurons, a cell type previously inaccessible to most scientists.
Image: Here human iPSC-derived neural stem cells (red) form polarized cellular rosettes with mitotic stem cells at the center. The rosettes mimic the polarized neuroepithelium that form during development in vivo and enable cellular studies of human forebrain neurogenesis. These iPSCs were directed to differentiate as stem cells of the cerebral cortex, the integrative and executive center of the human brain. Neural stems cells are labeled red with an antibody to Pax6, and dividing stems cells are labeled white with an antibody to phospho-histone H3. Gamma tubulin is labeled green, marking the apical surface of the stem cells. Image was acquired with a confocal microscope.
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A Glimpse of the Future
By Kristen Brennand, Salk Institute for Biological Studies
One exciting application of human iPSCs is studying the molecular mechanisms of complex diseases intractable by animal models, such neurological and psychiatric disorders. With iPSCs, researchers can generate neurons with the exact genotypes of patients. For example, recently Muotri et al. (2010) and Brennand et al. (2011) produced iPSC-derived neurons from patients with Rett's syndrome and schizophrenia, respectively. Remarkably, in both cases, these patient-derived neurons displayed disease phenotypes that could be treated with known therapeutics.
Image: Here, neurons derived from patients with Schizophrenia are imaged with confocal microscopy at 400X magnification. These iPSC-derived neurons express βIII-tubulin (red) and the dendritic marker MAP2AB (green). DAPI stains the nucleus blue.
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