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This week, while perusing my favourite news websites, I discovered that October is Down Syndrome Awareness month in the US. We Canadians however, have reserved our Down Syndrome Awareness week for the first week of November but nevertheless, this got me thinking about the current state of Down Syndrome research and what stem cell biologists have been up to in this field.
Down Syndrome is a genetic disorder characterized by an extra copy of chromosome 21, which means that any gene located on chromosome 21 would be present in three copies instead of the normal two. Gene expression in cells is tightly regulated and too little or too much expression of a particular gene can lead to harmful effects. Due to the over-expression of genes on chromosome 21, Down Syndrome patients have various health problems, developmental delays and learning disabilities.
Stem cell researchers have been busy studying Down Syndrome and have made significant progress over the past few months. This summer, a group of researchers reported in Nature the use of a technique for inactivating one copy of chromosome 21 in Down Syndrome pluripotent stem cells which reversed several cellular defects that could be seen in Down Syndrome cells. While exciting, this work did not shed any light on which specific genes on chromosome 21 contribute to defects seen in Down Syndrome patients. However, a few weeks ago another report in Nature identified the triplication of a specific gene known as Usp16 to cause, at least in part, defects in somatic stem cell populations in Down Syndrome mice.
Researchers found that Down Syndrome mice have a decreased number of haematopoietic stem cells, a 50% reduction in colony forming ability in vitro (a method to quantify stem cells within a given sample) and impaired multi-lineage engraftment of bone marrow cells compared to control animals. These results suggested a haematopoietic stem cell self-renewal deficit in Down Syndrome mice which means the ability of these mice to replenish their blood cells is diminished (red blood cells need to be replaced after approximately 120 days to stay healthy).
To determine whether the haematopoietic stem cell self-renewal defect is a result of Usp16 over-expression, the researchers used small interfering RNA technology (explained in this earlier post) to reduce the level of Usp16 gene expression in Down Syndrome mice to normal expression levels. They found that reduced Usp16 expression in haematopoietic stem cells restored the ability to form colonies in vitro, engraft into recipient mice and give rise to multipotent differentiation upon transplantation, tying Usp16 directly to the impaired function of the haematopoietic stem cells in Down Syndrome mice.
Defects were also found in neural progenitor cells (progenitor cells found in the brain) and the mammary epithelium of these mice. Both cell types have a reduced ability to form colonies in vitro that could be partially rescued by reducing the gene expression level of Usp16. The inability to fully restore the function of neural progenitor and mammary epithelial cells suggests that additional genes are likely involved in somatic stem cell impairment in these mice.
Declining function of somatic stem cells is a consequence of aging and the identification of somatic stem cell defects in a Down Syndrome model is particularly intriguing as Down Syndrome has been associated with an early onset of age-related disorders (discussed here). Down Syndrome patients experience early onset of conditions including Alzheimer’s disease, menopause and arthritis.
While much more work needs to be done, it is exciting that researchers have identified at least one premature aging mechanism (somatic stem cell impairment) in Down Syndrome and have tied this back to the triplication of the Usp16 gene. Mapping clinical aspects of Down Syndrome to specific genes opens the door to new potential therapeutic targets to alleviate premature aging for individuals living with Down Syndrome.
Research cited:
Jiang J., Jing Y., Cost G.J., Chiang J.C., Kolpa H.J., Cotton A.M., Carone D.M., Carone B.R., Shivak D.A. & Guschin D.Y. & (2013). Translating dosage compensation to trisomy 21, Nature, 500 (7462) 296-300. DOI: 10.1038/nature12394
Adorno M., Sikandar S., Mitra S.S., Kuo A., Di Robilant B.N., Haro-Acosta V., Ouadah Y., Quarta M., Rodriguez J. & Qian D. & (2013). Usp16 contributes to somatic stem-cell defects in Down’s syndrome, Nature, 501 (7467) 380-384. DOI: 10.1038/nature12530
Souroullas G.P. & Sharpless N.E. (2013). Stem cells: Down’s syndrome link to ageing, Nature, 501 (7467) 325-326. DOI: 10.1038/nature12558
Angela C. H. McDonald
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