OSTEOBLASTS AND HEMATOPOIETIC MICROENVIRONMENT

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Hematopoietic stem cell differentiation occurs in direct proximity to osteoblasts with in the bone marrow cavity. We hypothesize that this intimate physical association established early in life is to facilitate interactions between bone and hematopoietic cells. To test this hypothesis we will determine whether human osteoblasts are a source of essential hematopoietic growth factors. Our investigations will utilize a combination of co-culture and molecular biological approaches to determine whether cytokines derived from osteoblasts influence hematopoietic stem cell survival, proliferation and maturation. Toward these aims we have developed an primary human osteoblast purification and culture system which allows us to study these cells in isolation. Our preliminary results indicate that these cells support the survival and proliferation of primitive CD34+ cells, while apparently maintaining them in a primitive state. We hope to pin down what activity is responsible for this novel effect. The direct clinical relevance of these investigations includes: i) Is cytokine synthesis altered in response to marrow injury as in osteomyelitis and/or infections in surrounding tissues as in periodontal diseases? ii) If osteoblasts contribute to the maintenance of normal hematopoiesis, can we decrease the morbidity and mortality associated with bone marrow transplantation by altering osteoblast function? iii) And finally, one day these investigations may facilitate gene therapy for hematopoietic abnormalities by delineating the factors necessary for the survival of transduced hematopoietic stem cells.