Mammalian bone marrow (BM) is a complex mixture of lymphohematopoietic cells at multiple stages of development, in close proximity to a microenvironment comprising a heterogenous population of stromal cells and extracellular matrix molecules. Pluripotent stem cells (PSC) and their committed progeny rely on stromal cell contact and stromal cell- derived growth regulatory cytokines for normal development. The regulation of growth and development in PSC and their differentiated progeny of the granulocyte, monocyte, erythrocyte, and platelet lineages is fairly well understood. However, much less is known about PSC commitment to the B cell lineage and subsequent regulation of B cell precursor growth and development. During the last several years important progress has been made in developing BM stromal cell- dependent in vitro assays that support the growth and differentiation of human B cell precursors. A primary goal of this application is to determine the precise mechanisms by which stromal cells regulate normal B cell development and, in turn, whether B cell precursor adhesion regulates stromal cell gene expression.
The specific aims are: l) To elucidate the mechanism by which interleukins/cytokines and bone marrow stromal cell-derived molecules (e.g., vascular cell adhesion molecule-1) orchestrate the proliferation and/or differentiation of the two major subpopulations of B cell precursors: progenitor (pro)-B cells and precursor (pre)-B cells; 2) To characterize the functional contribution of bone marrow stromal cells to the adhesion, growth, and differentiation of B cell precursors, and to also determine whether B cell precursor adhesion stimulates protein tyrosine kinase activation and/or changes in cytokine gene expression in bone marrow stromal cells; and 3) To develop an in vitro model that recapitulates human B cell ontogeny from the earliest stages of lymphohematopoietic stem cell development (i.e. the pluripotent/lymphoid stem cell) to the final stage of B cell differentiation (i.e., plasma cell production and Ig secretion). The results from these studies will improve our understanding of how the immune system develops, and will facilitate a more precise dissection of the perturbations in B cell development that can lead to immunodeficiency and acute lymphoblastic leukemia.
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