Hematopoiesis is regulated by the hematopoietic microenvironment which is composed of hematopoietic cells, stromal cells, and soluble factors. Recent studies with long-term bone marrow culture have indicated that physical interaction between hematopoietic cells and stromal cells is crucial in establishing hematopoiesis in vitro and have demonstrated that adhesion molecules such as CD44 and VLA-4 are involved. We will define further adhesion molecules that are involved in the interaction of stromal cells with myeloid cells and lymphoid cells, the regulatory roles of these adhesion molecules, and how developing hematopoietic cells modulate the expression and function of different adhesion molecules. Adhesion between a panel of hematopoietic indicator cells and stromal cell clones will be examined as to involvement of known adhesion molecules and physicochemical characteristics. So far, we have identified three novel mechanisms of adhesion of a multipotential stem cell clone and a mast cell line to stromal cell clones. We will prepare blocking mAbs to stromal cells and hematopoietic cells to characterize the molecular basis of these adhesion pathways, examine their roles using long-term bone marrow culture, culture of a multipotential stem cell clone with stromal cell clones, and fibroblast coculture with mast cells. We will identify cDNA clones for the molecules involved in these adhesions pathways to study the structural basis of adhesion. We will further analyze using these systems the modulation of adhesion molecules during differentiation. We will examine whether differential expression of adhesion molecules in stromal cells regulates their abilities to generate myeloid progenitors in a clonal culture system. We will test the hypothesis that Steel/c-kit is involved in adhesion of mast cells to fibroblasts. We will prepare mAbs to the Steel product and examine their effects on adhesion of mast cells to fibroblasts and test the relationship of Steel/c-kit to two novel adhesion pathways we have found in the interaction of mast cells with stromal cells.
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