| Recent advances in stem cell biology may provide new approaches for the treatment of a number of regenerative diseases. These approaches could involve cell replacement therapy and/or drug treatment to stimulate the body's own regenerative capabilities by promoting survival, proliferation, migration/homing, and differentiation of endogenous stem/progenitor cells. This requires an improved ability to manipulate stem cell proliferation and differentiation, and a better understanding of the signaling pathways that control stem cell fate. Cell-permeable synthetic molecules have been shown to be extremely useful to regulate stem cell fate and investigate the underlying biology.;We have developed a series of cell-based high throughput screens targeting different biological systems, identified active molecules and defined their mechanism of action. These include: a novel pyrimidine derivative, SC1, which maintains murine embryonic stem cells (mESCs) in an undifferentiated, pluripotent state under chemically defined conditions in the absence of feeder cells, serum and LIF. SC1-expanded mESCs can be differentiated into cells of the three primary germ layers in vitro, and can also generate chimeric mice and contribute to the germ line in vivo. The process was found to involve dual inhibition of RasGAP and ERK1, and consequently activation of PI3K signaling pathway; a purine derivative, reversine, which reprograms lineage-committed mammalian myoblasts to multipotent cells that lose the expression of myogenic markers and can further differentiate into osteoblasts and adipocytes under lineage-specific inducing conditions. Biochemical and cellular experiments suggests that reversine functions as a dual inhibitor targeting two proteins---by inhibiting non-muscle myosin II (NMMII) reversine induces cells to accumulate at M phase, while by at the same time deacylating histone H3 by blocking MEK-dependent signaling; a Wnt agonist, BIO, which promotes the self-renewal of cardiac progenitors; a shh agonist, purmorphamine, which promotes the functional proliferation of human adult beta-cells; and a series of purine analogs that promote the functional proliferation of neonatal cardiomyocytes. Molecules of these kinds may not only facilitate practical applications of stem cells in research and therapy, but also provide new insights into the complex biology of stem cells. |
