The development and differentiation of hematopoietic stem cells into mature progeny is critically dependent on their interactions with the stromal elements of the bone marrow. Stromal cells produce and sequester into their extracellular matrix cytokines that are essential for stem cell division and differentiation.
The aim of this proposal is to determine whether localized proteolysis, mediated by plasminogen activators and/or plasmin (the product of plasminogen activation by plasminogen activators), is an integral part of the chain of events leading to the release of effector molecules required for stem cell division and differentiation. Plasminogen activator activity is modulated by specific inhibitors, specific enzyme receptors and matrix macromolecules which may either inhibit or potentiate activity. In this manner, controlled pericellular proteolysis in the bone marrow stromal microenvironment, functions to modulate haemopoiesis via the proteolytic release of effector molecules. The regulation of plasminogen activator and plasminogen activator inhibitor activity in normal myeloid cells, in myeloid leukemic cell lines and in bone marrow stromal cells by factors such as the colony stimulating factors, basic fibroblast growth factor and transforming growth factor beta will be investigated. The interaction of the plasminogen activators with stromal cells and matrices will be examined. This will include the identification of specific binding molecules for tissue plasminogen activator on the surfaces of cells and in the matrix. The ability of inhibitors of plasminogen activator to perturb either normal myeloid differentiation and cell division, or matrix-induced differentiation of leukemic cell lines will be examined. The data generated during this project will yield new insights into the regulation of both normal leukemic myelopoiesis.
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