A major risk in the regenerative medicine field is the potential of tumorigenesis in transplanted tissues. When transplanted, human embryonic stems invariably form tumors showing the natural tendency of these cells for uncontrolled cell growth. However, the natural counterparts of these cells that occur during human embryonic development rarely ever form tumors. This suggests that there are powerful embryonic programs that suppress unwanted cell growth as these cells differentiate into adult tissues. We have established a likely role for small molecules called microRNAs in this process. In the absence of microRNAs, the embryonic stem cells fail to differentiate into adult tissues and hence proliferate indefinitely. The goals of our CIRM grant are to uncover the specific microRNAs that are responsible for differentiation and the suppression of cell growth. During the period of this grant, we have made significant progress toward this goal. We have published two manuscripts on this work, both in high impact journals. One study was published in Nature Biotechnology where we show that a family of microRNAs can promote the de-differentiation of specialized cells back to unspecialized embryonic cells that than can be differentiated to all adult cell types. This work also led to a submission of a patent. The other study in Nature shows how another family promotes differentiation and suppresses proliferation of embryonic stem cells. Furthermore, it shows that the two families: one promoting de-differentiaton and the other promoting differentiation antagonize one another in the decision of whether to continue to remain undifferentiated and proliferate. Second, we have performed large screens to identify many other miRNAs that promote differentiation and de-differentiation both in mouse and human ES cells. We are now trying to complete these stories and prepare them for publication. Our findings provide insights into how one might use small RNAs to clinically manipulate cells in order to expand stem cells or promote their differentiation as needed to produce stable replacement tissues with diminished risk for tumor growth.