All of the cells of the blood are derived from a common ancestor. This cell is known as the Pluripotential Hematopoietic Stem Cell (PHSC). The differentiation of these stem cells occurs in a complex bone marrow micro-environment where accessory cells and growth factors interact with PHSC. PHSC are not undifferentiated cells. They are uniquely specialized cells, whose role is to provide progenitors for the various hematopoietic lineages in a demand-responsive manner, while protecting the stem cell pool from depletion. Our efforts are directed towards characterizing these pluripotential cells and understanding how their growth is regulated in the face of environmental demands for mature hematopoietic cells. Understanding these processes is critical for developing new strategies for bone marrow transplantation and gene therapy.

Three questions are being actively pursued: l.When is a stem cell a stem cell? Cells resembling stem cells can be isolated from different sources such as bone marrow, mobilized peripheral blood, cord blood and fetal liver. These cells differ in cytokine receptor and integrin expression, growth potential, homing properties and ability to grow in immunodeficient mice. The basis for these differences is unknown. We are trying to determine if they reflect intrinsic age-related differences between stem cells indicate different populations of cells that differ in growth potential. 2.What is the molecular basis for the pluripotential state? We are trying to distinguish between signals that cause cells to differentiate and those that cause them to replicate. We have shown that synergistic interactions between cytokines play an important role in determining the fate of stem cells. PCR-driven subtractive hybridization is being used to identify mRNAs expressed uniquely in stem cells. Differentially expressed messages have been characterized and we are trying to identify their protein products. 3. What is the role of stromal cells in maintaining the pluripotential state? We have developed a series of mouse stromal cells that support the growth of human hematopoietic progenitors. These cells are being used to identify the factor(s) that maintains the growth of human HSC. These lines will be used to determine if stromal-HSC interaction is required for the maintenance of pluripotentiality.