We will utilize the setting of bone marrow transplantation to study stem cell and progenitor differentiation by characterizing in detail the regulation of hematopoiesis following transplantation, and in particular will examine the role of granulocyte-monocyte- colony stimulating factor (GM-CSF) in engraftment. The bone marrow transplant patient provides a unique and important setting for studying the regulation of hematopoiesis. Unlike studies of adult bone marrow which reflect the expression of committed progenitors which have developed in a steady state, experiments with regenerating bone marrow post-transplantation can illuminate the control of the development of these progenitors from pluripotent stem cells. Information obtained from these studies may have direct relevance to the clinical success of the transplantation procedure, particularly those involving haploidentical transplants and T cell depletion of donor marrow.
Specific aims will be to: 1. Analyze the progenitor-adventitial cell interactions in the bone marrow transplant recipients. Measure the extent of defects in hematopoietic helper cell function in these patients. 2. Measure GM-CSF expression and production in hematopoietic helper cell fractions to determine the cause of helper cell defects. 3. Determine the genotype of functional helper cell subsets in recipient marrow samples. 4. Study the influence on in vitro colony growth of specific peripheral blood lymphoid populations and their soluble growth factors such as GM-CSF that develop posttransplantation, notably from patients undergoing graft-versus-host disease, delayed engraftment, or impending graft rejection. 5. Determine the roles of accessory cells, growth factors, and genetic identity in stem cell differentiation on an in vitro monolayer of stromal ST.1 fibroblasts. These studies will utilize the bone marrow transplant setting to analyze the interactions between hematopoietic stem cells and surrounding cells in hematopoietic differentiation. Through these experiments we hope to illuminate the control of hematopoiesis and to improve our understanding of engraftment in clinical bone marrow transplantation. We hope that our findings will help us to modify this important procedure so as to encourage rapid engraftment without the onset of graft-versus-host disease.
