REGULATORY GUIDANCE OF STEM CELL ENGINEERING: LYMPHOCYTE DEVELOPMENT MODELS
Rothenberg Laboratory, California Institute of Technology
by
Ellen V. Rothenberg, Principal Investigator/ Professor of Biology
Rochelle A. Diamond, Laboratory Manager/ Member of Professional Staff

OBJECTIVE

Stem cells are a natural, renewable source of precursors that can give rise to many different tissues and cells in the body. The ability to grow stem cells and then guide them to desired developmental outcomes would open new doors to future treatment of a variety of serious diseases. However, controlling what the stem cells do, and ensuring that they do it in a coordinated way, is vital. The potential for unlimited growth and for differentiation along multiple, potentially unwanted pathways are properties that stem cells share with cancer cells. The promise of stem cells for therapeutic use depends on understanding not only what kinds of positive triggers cause these cells to start differentiating, but also what kinds of mechanisms guarantee that their development can be controlled, so that as they differentiate they truly give up the more dangerous features of their stem-cell past.

One of the best places to study these safety mechanisms in action is during the differentiation of blood stem cells into T lymphocytes. Blood stem cells are probably the best-characterized adult stem cells known in biology. The path they take to become T lymphocytes (“T cells”) is especially well marked. There is good separation between distinct phases of development in this pathway, and there is clear demarcation of exact steps through which the precursor T cells give up the options to remain stem cells or to develop into other pathways. In the course of this process, the cells come remarkably close to conversion into leukemia cells. The key to normal T-cell development is that it incorporates extremely strong and efficient safety mechanisms that guide the cells past this danger. These safety mechanisms and the ways they can act compatibly with the generation of huge numbers of early T cells are profoundly interesting for stem-cell developmental engineering.

The Rothenberg group has now identified many of the important regulatory molecules that need to be activated or repressed in order to make this transition safely. Our research has shown how experimental changes in individual regulatory molecules can destabilize T-cell development and how signals from other regulatory molecules can restore correct development. The goal of this research program is now to determine exactly how these molecules work together, to coordinate the accurate conversion of stem cells to T cells and to make this process irreversible. The molecular and cellular tools are in hand to make this project successful. The general principles that emerge from this work should be applicable to many systems of directed differentiation from adult stem cells.