There are so many articles I see and don’t have time to write research highlights on and so many that I miss. Here’s what caught my eye this week.
Protein in embryonic stem cells controls malignant tumor cells (PNAS)
Adult stem cells seem to help some autoimmune and cardiovascular diseases (JAMA)
Adult stem cell changes underlie rare genetic disease associated with accelerated aging (Nature Chemical Biology)
Multiple articles on MicroRNA (Nature on skin differentiation; Cell Stem Cell on mesoderm differentiation; Nature Structural & Molecular biology on mechanism)
Those hunting for kidney stem cells might want to look in the tubule (Cell Stem Cell)
For more on these, see below.
(BTW: Pulling these together takes forever; so if it’s useful, please let me know. Also, we are, gradually, putting all these articles in our Journal Club, where you can add interesting articles as well.)
Adult stem cells seem to help some autoimmune and cardiovascular diseases
A metareview in JAMA suggests that stem cells from an adults bone or blood marrow could treat some patients for some patients for some autoimmune and cardiovascular disorders. A literature search first identified 926 articles, 579 were excluded as not original research; 24 were excluded as cancer related. Of the remaining 323 articles, 254 were excluded, mainly because they included three or fewer patients or were interim reports. Of the 69 remaining, 26 (on 854 patients) were for autoimmune disease. The study describes positive results, under certain treatment conditions, for multiple sclerosis, type I diabetes, and arthritis. It also describes positive results in coronary artery disease and heart attack. The article concludes, of course, that more conclusive clinical trials are needed.
From JAMA: “Their analysis suggests that stem cells harvested from blood or bone marrow may provide modest disease-ameliorating effects in selected patients with some autoimmune diseases and some cardiovascular disorders.”
Read about this article in HealthDayNews
Protein in embryonic stem cells controls malignant tumor cells
An article in PNAS by Mary Hendrix of Northwestern University shows that aggressive tumor cells express the embryonic gene, Nodal, but not another embryonic protein, Lefty. Exposing the tumor cells to Lefty reduced their tumorigenicity and triggered cell death
Read about this article in the Washington Post
Adult stem cell changes underlie rare genetic disease associated with accelerated aging
An article in Nature Cell Biology links stem cells to progeria, a disease in which very young children quickly accumulate symptoms of aging. Progeria is characterized by a mutated form of a protein called progeria, and it turns out that progerin activates genes involved in the Notch signaling pathway, a major regulator of stem cell differentiation. Progerin-producing mesenchymal stem cells rapidly differentiated into bone but not fat. Clinical symptoms of the disease include loss of fatty tissues and overgrowth of bone.
Also, work on the cells that help kidney regenerate has been published in Cell Stem Cell by Humphreys and Bonventre of Harvard. It concludes that those looking for adult kidney stem cells best look in the tubule.
MicroRNA is mega
Three articles show microRNAs roles in the proliferation and differentiation of stem cells: one, on skin, comes from the Fuchs lab at Rockefeller. The other, on cardiomyocytes, comes from Srivastava’s lab at the Gladstone; another from Blasco’s lab at the Spanish National Cancer Lab, shows that a lack of the microRNA processing machinery in mice decreases a gene-silencing program called methylation and are correlated with decreased expression of DNA methyl transferases. (For the first two, research highlights have been submitted to our web team and will appear on our site, or you can see below.)
MicroRNA switches off the proliferation of skin stem cells in mice
Rockefeller University researchers, publishing online in Nature, show that short strands of non-coding RNA, called microRNAs (miRNAs), regulate stem cells in the skin of mice.1 During gestation, proliferating stem cells in the skin’s basal layer start to differentiate and migrate outward to form the epidermis, protective layers that keep pathogens out and essential fluids in. Specifically, miRNA-203, one of hundreds of the tiny gene-regulatory molecules expressed in mammals, appears to signal the switch from proliferation to differentiation as skin develops in embryonic mice. The work is part of a broader effort to understand how the deregulation of normal skin growth can lead to diseases like cancer and psoriasis in humans.
First author Rui Yi, working with Elaine Fuchs, head of the Laboratory of Mammalian Cell Biology and Development, had previously identified more than 100 miRNAs specific to the outer layer of mouse skin and linked them to mammalian development2. The new research sought to determine the individual roles of some of those miRNAs.
MiRNAs disrupt protein synthesis by binding to gene transcripts (messenger RNAs) and so allow gene regulation to occur outside the nucleus. Yi showed that during embryonic development in mice, miRNA-203 is rapidly upregulated over a two-day period to become the most abundant miRNA in the suprabasal layers of the epidermis. Furthermore, this change in expression coincides with the period in which proliferating multipotent stem cells begin to migrate and differentiate to form the skin’s outer layers. Both observations suggest that miRNA-203 could play an important role the organ’s development.
To clarify its function, he created transgenic mice that overexpressed miRNA-203 in the skin’s basal layer; he also used a molecule called an antagomir, which binds to miRNA-203 and blocks its function. When miRNA-203 was overexpressed, the multipotent stem cells proliferated less and the skin of the live-born mice was markedly thinner—resembling that of mice that are deficient in a transcription factor called p63. Conversely, when miRNA-203 was blocked, the cells proliferated more and skin thickened.
Next, the researchers questioned how miRNA-203 was exerting these effects. Did it impair the function of stem cells? Indeed, they showed that miRNA-203 specifically impairs the proliferation of stem cells as they migrate from the basal to suprabasal layers. It does not seem to affect differentiation. And p63, a molecule known to be an essential regulator of stem-cell maintenance in epithelial tissue, proved to be its downstream target. Interestingly, both proteins are conserved across vertebrates, suggesting they’ve played an important biological role for about 400 million years.
Presently, the researchers hope to determine whether this miRNA-203-mediated on/off switch plays a role in human disease, in particular, squamous cell carcinoma. The work could also be extended to other tissues and other developmental stages to further elucidate the role of miRNAs in the regulation of stem cells.
[1] Yi, R., Poy, M.N., Stoffel, M., and Fuchs, E. A skin microRNA promotes differentiation by repressing “stemness.” Nature published online 2 March 2008;
doi: 10.1038/nature06642
[2] Yi, R., et al. Morphogenesis in skin is governed by discreet sets of differentially expressed microRNAs. Nature Genetics 38: 356-62 (2006)
MicroRNA sets cell fate
In the absence of short RNA molecules known as microRNAs, embryonic stem cells cannot differentiate, but how the 22-nucleotide molecules direct cells toward different fates is unclear. Reporting in Cell Stem Cell, Deepak Srivastava and colleagues of Gladstone Institute of Cardiovascular Disease and the University of California, San Francisco, describe how microRNAs (miRNAs) control one of a cell’s earliest decisions, the specification into the three germ layers (ectoderm, mesoderm, and endoderm) which go on to form all the body’s organs.
miRNAs stop gene expression by binding to gene transcripts (messenger RNA) and either blocking the transcripts’ translation into protein or flagging it for degradation. To pinpoint miRNAs that promote differentiation, Srivastava’s group compared miRNAs in ES cells with those in differentiating cardiomyocytes derived from ES cells. They found nine that were particularly abundant in cardiomyocytes, including two, miR-1 and miR-133, already known to be important for heart development. These miRNAs appeared specifically in precardiac mesoderm and within 4 days of embryoid body formation (clumps of cells that appear when ES cells are allowed to differentiate).
To work out exactly what the miRNAs were doing, mouse ES cells were infected with a virus causing them to express miR-1 or miR-133 earlier than usual. Microarray data showed that expression of either miRNA caused many genes to be mis-expressed; many early endoderm genes were downregulated; some neuroectoderm genes were upregulated, but markers for differentiated neurons decreased. These observations indicate that the two miRNAs boost mesoderm specification while simultaneously suppressing differentiation within the other gene layers. Further experiments pinned one mechanism on the suppression of a protein called Delta like-1, a Notch ligand that normally promotes neural differentiation. Indeed, knocking down Delta like-1 expression had a similar effect to adding miR1.
The group depleted miR-1 and miR-133 by deleting a protein required for their expression and found that differentiation of mesoderm was weak and delayed. Introducing miR-1 brought expression of Brachyury, a marker of early mesoderm, back to wild type levels; miR-133 was about half as effective, implying that they both contribute to progression of mesodermal differentiation.
This is a unique insight into how miRNAs can fine tune differentiation patterns. The authors suggest that miRNAs should be useful in directing ES cells toward certain cell fates.
Reference:
Ivey, K., et al., MicroRNA Regulation of Cell Lineages in Mouse and Human Embryonic Stem Cells, Cell Stem Cell (2008), doi: 10.1016/j.stem.2008.01.016