http://repub.eur.nl/res/aut/7263/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/30840/ 2003-10-29T00:00:00Z The hematopoietic system is a cell renewal system in which mature peripheral blood cells with a limited life span are continuously replenished by proliferation and differentiation of lineage-specific progenitor cells derived from scarce pluripotent hematopoietic stem cells. The process of blood cell formation, hematopoiesis, takes approximately 20-30 cell divisions and takes mainly place in the bone marrow (BM) in adult mammals. In fetal hematopoiesis, liver and spleen also play an important role, whereas there is still residual hematopoiesis in the spleen of adult mice. The process of hematopoiesis is tightly controlled by hormone like proteins the hematopoietic growth factors (HGFs), by other cytokines, by complex interactions between hematopoietic cells and stromal cells in the BM, via extracellular matrix molecules and cell-cell interactions through specialized adhesion molecules. Different models have been developed in which stem cell commitment and differentiation are described as either a stochastic/random process or in which stem cell fate is regulated by external stimul. http://repub.eur.nl/res/pub/8938/ 1998-01-01T00:00:00Z Radiation-induced pancytopenia proved to be a suitable model system in mice and rhesus monkeys for studying thrombopoietin (TPO) target cell range and efficacy. TPO was highly effective in rhesus monkeys exposed to the mid-lethal dose of 5 Gy (300 kV x-rays) TBI, a model in which it alleviated thrombocytopenia, promoted red cell reconstitution, accelerated reconstitution of immature CD34+ bone marrow cells, and potentiated the response to growth factors such as GM-CSF and G-CSF. In contrast to the results in the 5 Gy TBI model, TPO was ineffective following transplantation of limited numbers of autologous bone marrow or highly purified stem cells in monkeys conditioned with 8 Gy TBI. In the 5 Gy model, a single dose of TPO augmented by GM-CSF 24 h after TBI was effective in preventing thrombocytopenia. The strong erythropoietic stimulation may result in iron depletion, and TPO treatment should be accompanied by monitoring of iron status. This preclinical evaluation thus identified TPO as a potential major therapeutic agent for counteracting radiation-induced pancytopenia and demonstrated pronounced stimulatory effects on the reconstitution of immature CD34+ hemopoietic cells with multilineage potential. The latter observation explains the potentiation of the hematopoietic responses to G-CSF and GM-CSF when administered concomitantly. It also predicts the effective use of TPO to accelerate reconstitution of immature hematopoietic cells as well as possible synergistic effects in vivo with various other growth factors acting on immature stem cells and their direct lineage-committed progeny. The finding that a single dose of TPO might be sufficient for a clinically significant response emphasizes its potency and is of practical relevance. The heterogeneity of the TPO response encountered in the various models used for evaluation points to multiple mechanisms operating on the TPO response and heterogeneity of its target cells. Mechanistic mouse studies made apparent that the response of multilineage cells shortly after TBI to a single administration of TPO is quantitatively more important for optimal efficacy than the lineage-restricted response obtained at later intervals after TBI and emphasized the importance of a relatively high dose of TPO to overcome initial c-mpl-mediated clearance. Further elucidation of mechanisms determining efficacy might very well result in a further improvement, e.g., following transplantation of limited numbers of stem cells. Adverse effects of TPO administration to myelosuppressed or stem cell transplanted experimental animals were not observed.