Scientific Report 2006

Chemistry

Chemical and Functional Genomic Approaches to Regenerative Medicine

S. Ding, R. Abu-Jarour, R. Ambasudhan, C. Desponts, N. Emre, H.S. Hahm, S. Hilcove, J. Hsu, M. Kim, Y. Shi, S. Takanashi, W. Xiong, Y. Xu, S. Yao, D. Yue, Y. Zhao, X. Zhu

Recent advances in stem cell biology may make possible new approaches for the treatment of a number of diseases, including cardiovascular disease, neurodegenerative disease, musculoskeletal disease, diabetes, and cancer. These approaches could involve cell replacement therapy and/or drug treatment to stimulate the body’s own regenerative capabilities by promoting survival, migration/homing, proliferation, and differentiation of endogenous stem/progenitor cells. However, such approaches will require identification of renewable cell sources of engraftable functional cells, an improved ability to manipulate proliferation and differentiation of the cells, and a better understanding of the signaling pathways that control the fate of the cells.

Equipped with large arrayed molecular libraries—combinatorial chemical libraries (>100,000 discrete and diverse small molecules), cDNA overexpression libraries (>30,000 human and mouse genes) and small interfering RNA libraries (targeting >20,000 human and mouse genes)—and a high-throughput screening platform, we are developing and integrating chemical and functional genomic tools to study stem cell biology and regeneration. We screen these libraries to identify small molecules and genes that can control the fate of stem cells in various systems, including (1) self-renewal, as well as directed neuronal, cardiac, and pancreatic differentiations of pluripotent mouse and human embryonic stem cells; (2) directed neuronal differentiation and subtype neuron specification of human and rodent neural stem cells; (3) directed differentiation of mesenchymal stem cells to osteogenic, adipogenic, chondrogenic, and myogenic lineages; (4) functional proliferation of cardiomyocytes and islets/beta cells in adults; (5) cellular plasticity and dedifferentiation of lineage-restricted somatic cells; and (6) developmental signaling pathways.

In addition, we are doing systemic biochemical and cellular studies, including detailed investigations of structure-activity relationships, affinity chromatography for target identification, genome-wide expression analysis with microarrays, and cDNA and/or RNA interference complementation screens to map signaling pathways to characterize the molecular mechanism of these identified small molecules and genes.

Recent examples of small molecules of interest include neuropathiazol, which can direct differentiation of primary rat adult neural stem cells selectively toward neurons; pluripotin, which can sustain self-renewal of murine embryonic stem cells in a chemically defined medium; and a purine analog that functions as a synergistic Wnt pathway agonist and can induce Xenopus axis duplication in combination with Wnt8. These studies may ultimately facilitate the therapeutic application of stem cells and the development of small-molecule drugs to stimulate tissue and organ regeneration in vivo.

Publications

Warashina, M., Min, K.H., Kuwabara, T., Huynh, A., Gage, F.H., Schultz, P.G., Ding, S. A synthetic small molecule that induces neuronal differentiation of adult hippocampal neural progenitor cells. Angew. Chem. Int. Ed. 45:591, 2006.

Zhao, Y., Clark J., Ding, S. Genomic studies in stem cell systems. Curr. Opin. Mol. Ther. 7:43, 2005.