Scientific Report 2007

Chemistry

Chemical and Functional Genomic Approaches to Regenerative Medicine

S. Ding, R. Abu-Jarour, R. Ambasudhan, R. Coleman, C. Desponts, H.S. Hahm, S. Hilcove, J. Hsu, T. Lin, Y. Shi, W. Xiong, Y. Xu, X. Zhu

Recent advances in stem cell biology may make possible new approaches for the treatment of a number of illnesses, 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 a high-throughput screening platform and large arrayed molecular libraries—combinatorial chemical libraries, genome-scale cDNA libraries, and small interfering RNA libraries—we are developing and integrating chemical and functional genomic tools to study stem cell biology and regeneration. We screen these libraries to identify and further characterize small molecules and genes that can control stem cell fate in various systems, including (1) self-renewal regulation of embryonic and adult stem cells; (2) directed and stepwise differentiation of embryonic stem cells toward neuronal, cardiac, and pancreatic lineages; (3) directed neuronal differentiation and subtype neuronal specification of human and rodent neural stem cells; (4) cellular plasticity and reprogramming of lineage-restricted somatic cells to more primitive precursor cells; (5) functional proliferation of adult cardiomyocytes and pancreatic beta cells; (6) developmental signaling pathways and epigenetic mechanisms (histone and DNA de/methylation); and (7) development of new technologies for stem cell derivation and gene targeting.

In addition, we are characterizing the molecular mechanism of these identified small molecules and genes by using various approaches, including detailed investigations of structure-activity relationship, affinity chromatography for target identification, transcriptome profiling, proteomics analysis, chemical/genetic epistasis, and biochemical and functional assays in vitro and in vivo. So far, we have identified and are characterizing functional small molecules and/or genes in each of the distinct biological processes previously mentioned that involve regulation of stem/progenitor cells.

More recent examples include identification and characterization of distinct small molecules for self-renewal of human embryonic stem cells and clonal expansion/survival; dopaminergic neuron specification from mouse embryonic stem cells; derivation of rat embryonic stem cells; reprogramming of neural cells to a pluripotent state; definitive endoderm and pancreatic induction; chemically defined monolayer conditions for self-renewal of embryonic stem cells and their directed differentiation to cardiac lineages; proliferation of human beta cells; and regulating Wnt signaling. 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

Chen, S., Do, J.-T., Zhang, Q., Yao, S., Yan, F., Peters, E.C., Schöler, H.R., Schultz, P.G., Ding, S. Self-renewal of embryonic stem cells by a small molecule. Proc. Natl. Acad. Sci. U. S. A. 103:17266, 2006.

Emre, N., Coleman, R., Ding, S. A chemical approach to stem cell biology. Curr. Opin. Chem. Biol. 11:252, 2007.

Yao, S., Chen, S., Clark, J., Hao, E., Beattie, G.M., Hayek, A., Ding, S. Long-term self-renewal and directed differentiations of human embryonic stem cells in chemically defined conditions. Proc. Natl. Acad. Sci. U. S. A. 103:6907, 2006.

Zhang, Q., Major, M.B., Takanashi, S., Camp, N.D., Nishiya, N., Peters, E.C., Ginsberg, M.H., Jian, X., Randazzo, P.A., Schultz, P.G., Moon, R.T., Ding, S. Small-molecule synergist of the Wnt/β-catenin signaling pathway. Proc. Natl. Acad. Sci. U. S. A. 104:7444, 2007.

Zhao, Y., Ding, S. A high-throughput siRNA library screen identifies osteogenic suppressors in human mesenchymal stem cells. Proc. Natl. Acad. Sci. U. S. A. 104:9673, 2007.