. Synthetic small molecules that control stem cell fate. Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7632-7. PubMed.

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  1. This paper reports interesting data on the handles that might control the differentiation and phenotype of stem cells. The authors used a high-throughput phenotypic screen to identify a small synthetic molecule called TWS119, which induced transformation of a considerable percentage of mouse embryonic stem cells into neurons. Upon further characterization of this compound, the authors demonstrated that this molecule is a pyrrolpyrimidine and that its main target is glycogen synthase kinase (GSK)3β, a well-known kinase in Alzheimer disease.

    In various neurodegenerative diseases, the loss of distinct neuronal populations causes severe neurological symptoms. Hence, the possibility of replacing these lost cells and integrating them again in existing neuronal circuits is an attractive, yet complex therapeutic avenue. In addition, several studies have now shown that in the adult and even aging brain, neurogenesis continues to occur, albeit limited in number and only in two locations, i.e., the subventricular zone and the hippocampus (Heine et al., 2003, in press). In other brain areas like the cortex, adult proliferation occurs, as well, but here it gives rise to glia cells. For some reason, adult neurogenesis is not possible in other brain areas.

    Although relatively little is known to date about the factors that control—and within the brain, in fact prevent—the differentiation of newborn cells into a neuronal phenotype, another attractive strategy would be to "recruit" the endogenous potential of the brain's stem cells for repair in areas other than the hippocampus. In my view, the currently described molecules are very interesting candidates for such approaches.

    Stem cell differentiation clearly depends on the surrounding conditions, and in the present study, indeed, was limited to selected cell populations, i.e., P19 cells and primary mouse ESCs. Furthermore, treatment with 1 μM TWS119 caused about 30-40 percent of the cells to differentiate in neurons, whereas, surprisingly, transient treatment for two days followed by two more days of compound-free incubation resulted in even higher (40-60) percentages of neurons. Apparently, extended exposure of neural progenitors to early differentiation signals affects late-stage neuronal maturation. Moreover, in primary mouse ESCs, treatment with an even lower dose caused neuronal differentiation in 50-60 percent of the cells. Clearly, this molecule must be further tested to determine whether it can exert similar effects in other cells or cell lines and model systems.

    The finding that TWS119 is a target for GSK3b is intriguing. At the same time, many proteins are phosphorylated by GSK3, so it could be rather unspecific. GSK3 is a well-conserved, generally active kinase that modifies the function of a variety of proteins. It is one of the candidates for producing excessive phosphorylation of tau, which may harm or even protect neurons in Alzheimer disease (Spittaels et al., 2000). In addition to the affinity studies and the suggestions of a possible role in the Wnt pathway or the control of bHLH transcription factors, further functional and biochemical characterization is needed before this TWS molecule can be further implicated in tau phosphorylation. As in other studies, such a role would be consistent with the suggested close interplay between neuronal (de)differentiation processes, cytoskeletal plasticity and tau alterations, processes that occur both in early development as well as in neurodegenerative conditions like Alzheimer¡¦s disease.

    Overall, this paper is one of the first to identify possible (synthetic) candidate molecules that could, together with existing biological compounds, bear relevance for triggering (endogeneous) stem cell division and differentiation into a neuronal phenotype. Clearly, more information on TWS119 regulation and the uniformity of its working mechanism is needed, in addition to the important question of whether similar effects can be obtained upon local application in in-vivo approaches.

    References:

    . Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J Biol Chem. 2000 Dec 29;275(52):41340-9. PubMed.

    View all comments by Paul J. Lucassen

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  1. Small Molecules Turn Stem Cells into Neurons, Targeting GSK3β