Grant: Operating Grant

A feature unique to stem cells is their ability to copy themselves through a process known as self-renewal, which enables them to regenerate tissue. Self-renewal is essential for treatments aimed at expanding normal stem cell populations for life-saving procedures such as bone marrow transplants. Despite its importance, this process is not well understood, especially in hematopoietic stem cells (HSC) of the blood. Using viruses that stifle the production from a given gene, I have recently identified the cell fate determinant Msi2 as an essential regulator of mouse HSC. Though these results point to a possible application for Msi2 in achieving HSC expansion, such a strategy is dependent on the demonstration that it's function is similar in the more clinically relevant human setting. In the proposed research I will elucidate the role of Msi2 in human HSC through strategies that modulate its levels in human hematopoietic cells. By specifically elevating Msi2 levels in discrete cell types, I will explore how this protein functions in promoting stem cell self-renewal and/or imparting HSC characteristics to non-stem cells. I will also apply gene knockdown techniques to detail the effects of Msi2 loss on HSC self-renewal, proliferation and cell death. Lastly, a tagging approach will be implemented to allow the isolation of cells that normally have high levels of Msi2. We will explore whether using this strategy the elevated presence of Msi2 under different growth conditions can be used to purify HSCs. Such a demonstration would not only provide an important proof of principle for future drug screens to identify potent Msi2 activating compounds for use in HSC expansion protocols but could also begin to identify some of the regulators of Msi2 itself. Together, these studies will provide an in-depth understanding of the function of Msi2 in human HSCs, knowledge that could be used to harness the self-renewal process in regenerative therapies.