Mechanisms of Stem Cell Fate Decisions

Stem cells can mature into a diverse range of specialized cell types, providing exciting possibilities for regeneration of different tissue types. Many disorders can conceivably be treated by transplanting stem cells to replace the defective cells. However, several disorders affect a specific cell type, while other cells and tissues in the same patient are functioning normally. Examples of such cell type-specific cases are Parkinson’s disease, diabetes and anemia. A fundamental challenge in using stem cells to treat disease is to be able to steer their maturation into the specific cell type needed. Maturation into the wrong cell type may cause problems due to uncontrolled growth or immune rejection. For example, a blood stem cell transplant intended to treat anemia would be optimally efficient and safe if the transplanted cells could be directed to generate red blood cells without also producing T cells. Another major limitation of transplantation therapy is the shortage of cells for clinical use. This too could be alleviated by efficient generation of the desired cell type.

This proposal investigates the regulation of stem cell maturation into specific functional cell types. We are using blood cell development as a model system. Bone marrow transplantations, containing blood stem cells, have been used clinically for many years and are among few routinely performed cell-based therapies. The cumulative experience from years of clinical use together with decades of research on blood stem cell maturation makes this a strong model system for understanding both basic stem cell biology and clinical stem cell applications.

The many years of research on blood cell maturation has allowed the generation of a basic road map, complete with intersections indicating a choice in maturation pathway. As stem cells mature, choices are made along the way to become, for example, a T cell or a red blood cell. Scientists have identified signposts at these intersections that help mark some of the choices. These signposts are useful both as diagnostic tools to determine where cell maturation went wrong, and as targets for drugs when trying to promote one choice over another. Currently, we do not know when and how these choices are made under normal conditions and what goes wrong in various disorders. Our ability to direct or redirect cell fates upon transplantation or in cancer is therefore absent or inefficient. The goal of this proposal is to better define the intersections and signposts in blood cell development. We will generate new tools and methods to study stem cell maturation, and attempt to identify maturation stages and targets that will be useful to diagnose and treat blood-related disorders and increase the efficiency and safety of stem cell transplantation.