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May 22, 2014

Speeding Maturation of Induced Neurons Yields Better Disease Models

Speeding Maturation of Induced Neurons Yields Better Disease Models

Mature nerve cells generated from human cells using enhanced transcription factors. [Fahad Ali]

  • Although skin cells may be reprogrammed to form other cell types such as nerve cells, the “adult” status of the cell you start with may be lost along the way, perhaps irretrievably. That is, a reprogrammed cell may linger in an immature state. Instead of functioning like a fully developed cell, it may look as though it came from an embryo. Such a cell would be of little use in modeling the diseases that afflict adults.

    For example, the methods used to generate nerve cells from patient fibroblasts tend to yield low numbers of cells, and those that are produced are not fully functional. Because these cells remain incompletely differentiated, they have limited potential as models of disease. To date, these cells—induced neurons—have been poor substitutes for cortical neurons, which could model stroke, or motor neurons, which could model motor neuron disease. Suitable models for Alzheimer’s and Parkinson’s are also lacking.

    A new method of generating mature nerve cells from skin cells, however, has been developed. It could, in the near term, be used to improve models of age-related diseases such as Alzheimer’s and Parkinson’s. In addition, it could eventually generate mature nerve cells for transplantation into patients with a range of neurodegenerative diseases.

    The method, developed by researchers at the University of Cambridge, was described online May 12 in Development, in an article entitled “The phosphorylation status of Ascl1 is a key determinant of neuronal differentiation and maturation in vivo and in vitro.” (The same article is scheduled to appear May 27 in print.)

    By manipulating the signals that transcription factors send to the cells, the researchers, led by Anna Philpott, Ph.D., were able to promote cell differentiation and maturation, even in the presence of conflicting signals that were directing the cell to continue dividing. Specifically, the researchers accomplished the cell-cycle-dependent phosphorylation of a key reprogramming transcription factor, Ascl1, on multiple serine-proline sites. This multisite phosphorylation is a crucial regulator of the ability of Ascl1 to drive neuronal differentiation and maturation in vivo in the developing embryo.

    The researchers arrived at this approach after studying how nerves form in developing tadpoles. “A phosphomutant form of Ascl1 shows substantially enhanced neuronal induction activity in Xenopus embryos,” the authors wrote. “Mechanistically, we see that this un(der)phosphorylated Ascl1 is resistant to inhibition by both cyclin-dependent kinase activity and Notch signaling, both of which normally limit its neurogenic potential.”

    The main result reported by the authors was as follows: “The use of phosphomutant Ascl1 in place of the wild-type protein significantly promotes neuronal maturity after human fibroblast reprogramming in vitro.”

    To arrive at such results, suggested Dr. Philpott, “not only do you have to think about how you start the process of cell differentiation in stem cells, but you also have to think about what you need to do to make differentiation complete—we can learn a lot from how cells in developing embryos manage this.”

    Dr. Philpott and her collaborators are aware that the protein control mechanisms that promote neuron maturation are similar to those involved in the maturation of important cells in other tissues such as pancreatic islets, the cell type that fails to function effectively in type 2 diabetes. As well as making more mature nerves, Dr. Philpott's lab is now using similar methods to improve the function of insulin-producing pancreas cells for future therapeutic applications.

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