Formation of blood cells (hematopoiesis) is essential for maintain the continuity of immunity, gas transport and other essential functions. An increased understanding of hematopoiesis is vital for continued improvement in the treatment of human diseases, such as many leukemias where the treatment of choice includes supralethal chemo-irradiation and bone marrow transplantation to reconstitute the hematopoietic system. In addition, the toxicity induced by many of the chemotherapeutics results in an increased risk of bacterial infections and is frequently a dose- limiting complication. However, many questions remain unanswered concerning the identity of the stem and hematopoietic progenitor cells (HPC) and the growth factors controlling their proliferation and differentiation. Uteroferrin (UF), a protein secreted by the uterine epithelium of pigs and human placenta has hematopoietic growth factor activity. UF exists as a 35 kD polypeptide, but can be found as a heterodimer (Rose) associated with UF-associated proteins (UFA). Both UF and Rose can stimulate HPC from human and pig liver and bone marrow can protect and/or enhance recovery of the hematopoietic system following chemotherapy. The proposed experiments will isolate HPC from liver, bone marrow and primordial germ cells of fetal pigs with the aims of: 1) investigating the interactions between UF, Rose, UFA and other hematopoietic growth factors on the expansion of HPC in vitro; 2) characterization of responsive HPC pools and their developmental regulation; and 3) determination of the ability of these proteins to modulate the hematopoietic differentiation of primordial germ cells. In addition, in vivo experiments in young pigs undergoing chemotherapy will: 4) determine the ability of UF and Rose to enhance absolute HPC number in normal and myelosuppressed pigs; and 5) determine the ability of UF and Rose to protect and/or enhance recovery of the hematopoietic system following chemotherapy. Results will enhance our understanding of fetal hematopoiesis and may facilitate the clinical use of these proteins for the ex vivo expansion of hematopoietic stem cells for transplantation and/or their use as positive regulators of hematopoiesis to protect or stimulate recovery of the myeloid and lymphoid systems following chemotherapy.
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