title: Human haematopoiesis in steady state and following intense perturbations.
abstract: Haematopoiesis is comprised of multiple stages, originating from pluripotent stem cells through intermediate progenitors to mature differentiated cells. Consequently, during the development of blood cells numerous sites are potentially exposed to the intense perturbations induced by anticancer chemotherapy. However, little is known about human haematopoietic stem cell kinetics in health and following cytotoxic perturbations. Here we reconstruct the complex in vivo dynamics of haematopoietic populations, including the elusive pluripotent stem cells, with a detailed mathematical representation of the marrow biology. The bone marrow kinetic parameters were estimated by using white blood cell counts routinely collected in patients during high dose chemotherapy (HDCT) followed by autologous peripheral blood stem cell transplantation and granulocyte colony stimulating factor (G-CSF) injections. Studying the model performance under a wide variety of parameter values reveals that bone marrow is surprisingly robust in the physiologically feasible parameter space. We infer that the human haematopoietic pluripotent stem cell density is approximately 1 in 2 x 10(5) mononuclear cells and that most of these cells are quiescent, dividing once in 3-4 weeks. Our results suggest that the re-infused stem cell content is relatively high (10(4) kg-1 or 1/300 of CD34+ cells) which contributes to both the long-term marrow re-population as well as to short-term support. This study implies that, in most patients, the pluripotent population recovers within 4 months following HDCT. The proposed model accurately predicts the bone marrow dynamics over a wide range of perturbations caused by clinical interventions. It provides valuable insights about the haematopoietic regeneration capacity, predicts the effect of G-CSF manipulation and of ex vivo graft expansion in improving transplantation procedures, and may have implications for effective stem cell gene therapy.
authors.affiliation: Mathematical Modelling Group, Edinburgh University Department of Oncology, Western General Hospital, Edinburgh, U.K. E.Shochat@ed.ac.uk
authors.forename: Eliezer
authors.initials: E
authors.lastname: Shochat
authors.forename: Salomon M
authors.initials: SM
authors.lastname: Stemmer
authors.forename: Lee
authors.initials: L
authors.lastname: Segel
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D016026:Bone Marrow Transplantation / Q000502:physiology; D001943:Breast Neoplasms / Q000097:blood / Q000628:therapy; D003131:Combined Modality Therapy; D003198:Computer Simulation; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007958:Leukocyte Count; D008954:Models, Biological; D039904:Pluripotent Stem Cells / Q000378:metabolism / Q000502:physiology; D012189:Retrospective Studies
chemical_list: D016179:Granulocyte Colony-Stimulating Factor