A New Era for Disease Modeling and Drug Screening
December 29, 2008 by Aaron Cheung
Induced Pluripotent Stem (iPS) cells are cells that have been reprogrammed from skin fibroblasts back to a state reminiscent of Embryonic Stem (ES) cells. Human iPS cells were first discovered back in November 2007 by pioneer Dr. Shinya Yamanaka at Kyoto University (reported in scientific journal Cell in November 2007). iPS cells are thought to hold the same potential as ES cells in regenerative medicine such as disease modeling, drug screening, and cell replacement therapy, but with additional advantages as it bypasses the ethical issues relating to the use of human embryos.
I blogged about the promise of iPS cells a few months ago and it appears that progress is well on its way. The first step towards banking disease-specific pluripotent stem cells was led by Dr. George Daley, at Harvard Stem Cell Institute, who successfully made a handful of iPS cells from diseased patients. Since then, additional studies, such as that from Dr. Kevin Eggan, at the Harvard Stem Cell Institute, have made more iPS cells from patients affected with Amyotrophic Lateral Sclerosis (ALS) and was able to subsequently differentiate those iPS cells into motor neurons, the affected cell type in ALS (reported in the scientific journal Science in August 2008)
As promising as these studies have been, it is not quite enough to merely make the iPS cells from diseased patients themsleves. The gold question still remains, whether iPS cells will be able to fulfil its initial promise in regenerative medicine. Shortly after the scientific journal Science named iPS cells the breakthrough of the year in 2008, scientists from University of Wisconsin-Madison, Dr. James Thomson and Dr. Svendsen published an elegant paper in the scientific journal Nature where they have generated iPS cells from patients affected with Spinal Muscular Atrophy (SMA).
SMA is one of the most common inherited forms of neurological disease leading to infant mortality. Genetically, SMA is caused by a loss-of-function mutation in the gene encoding the protein, survival motor neuron (SMN). Patients exhibit selective loss of lower motor neurons resulting in muscle weakness, paralysis and often death.
In this study, they were able to differentiate the iPS cells from SMA patients into motor neurons and were able to show that these motor neurons showed abnormal phenotypes including a decrease in the actual number of motor neurons as well as the size of the motor neuron being smaller. Moreover, they were able to show that two drugs (Valporic Acid and Tobramycin) that are known to increase the SMN protein recapitulated their expected effects as neurons treated with these two drugs showed increased SMN protein levels.
In summary, this is the first and a very important proof-of-principle study that shows that iPS cells can be used for disease modeling and drug screening. Very exciting times indeed.
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Rett Syndrome and induced Pluripotent Stem cells goes “Green”
June 17, 2009 by Aaron Cheung
Stem cell researchers at The Hospital for Sick Children have now devised a method, reported in the scientific journal Nature Methods, that will facilitate the generation of induced Pluripotent Stem (iPS) cells. I have previously blogged about the promise of iPS cells (see related articles). iPS cells are cells which have been reprogrammed from a differentiated somatic cell (such as your skin cells) to a pluripotent stem cell (like an embryonic stem cell, only that you don’t need to use embryos!). The generation of iPS cells is inherently very rare which occurs at a frequency of about 0.01% meaning you can generate about one iPS cell line out of hundred thousand cells. Out of which, many lines fail to satisfy the different rigorous tests necessary to be given the prestigious name of “iPS cell”.
A group led by Dr. James Ellis, and lead author Dr. Akitsu Hotta, at The Hospital for Sick Children has generated a reporter, named EOS, that will facilitate the generation of iPS cells for both mouse and human. The reporter has DNA elements (called promoters) that will drive the expression of a fluorescent protein (GFP) and an antibiotic resistance gene (puromycin) that will only turn on in pluripotent stem cells, but remain off in differentiated cells. Therefore, scientists can now generate iPS cells from different sources and the iPS cells will literally “light up with a green colour” once reprogramming has been achieved. Furthermore, by adding puromycin to your culture, it will keep the iPS cells in a pluripotent state as iPS cells will normally spontaneously differentiate.
To demonstrate the applicability of EOS, Ellis also derived iPS cells from patients who have a neurodevelopmental disorder called Rett Syndrome. Rett Syndrome is an Autism Spectrum Disorder which affects almost exclusively females at an incidence of 1 in 10,000 and is one of the leading causes of mental retardation in girls. These Rett Syndrome iPS cells were green when placed under a fluorescent microscope and Ellis demonstrated that neurons can be generated from these Rett Syndrome iPS cells, the cell type affected in Rett Syndrome.
In conclusion, the EOS reporter will facilitate the generation of iPS and will be particularly useful for new labs going into this rapidly developing field. Furthermore, Rett Syndrome iPS cells that were also generated in this study will be invaluable for future drug screens that may be beneficial to those with Rett Syndrome.
Article:
Hotta, A. et al. Isolation of human iPS cells using EOS lentiviral vectors to select for pluripotency. Nature Methods 6, 370–376 (2009).
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[...] iPS cells from patients to model human diseases which I have blogged in my last two blogs. Personalized iPS cells will allow one to perform drug screens that are specific for each patient. [...]
[...] stem cells for uses such as disease modeling, drug screening, and hopefully one day, cell replacement therapy. As promising as these iPS cells were, they had severe drawbacks, which included the requirement [...]
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