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.

(A)Symmetric Stem Cell Replication and Cancer

“…doi:10.1371/journal.pcbi.0030053.g004 stimulation and the microenvironment within the SC niche together impose differentiation on one or both daughter cells that result from an SC division. However, the tendency of SCs to self-renew will ensure that if the SC pool is depleted (e.g., with high-dose chemotherapy), the remaining SCs can expand to occupy the available niches [40].…”

G-CSF Control of Neutrophils Dynamics in the Blood

“…Indeed, numerous mathematical models of the neutrophil production-also termed granulopoiesis-have been suggested over the years (Rubinow and Lebowitz, 1975;Lajtha et al, 1962;King-Smith and Morley, 1970;Blumenson and Bross, 1979;Abkowitz et al, 1996;Bernard et al, 2003;Zamboni et al, 2001;Krzyzanski et al, 1999;Shochat and Stemmer, 2002;Ostby et al, 2003;Scholz et al, 2005;Vainstein et al, 2005;Panetta et al, 2003;Wang et al, 2001;Foley et al, 2006;Haurie et al, 2000). Each of the models showed a good agreement with some empirical data.…”

“…Each of the models showed a good agreement with some empirical data. A number of these models were specifically developed to mathematically capture the detailed biology of the bone marrow (Rubinow and Lebowitz, 1975;Blumenson and Bross, 1979;Abkowitz et al, 1996;Shochat and Stemmer, 2002;Vainstein et al, 2005). Such models are intrinsically high dimensional, nonlinear and often contain large parameter sets.…”

Somatic mutations and the hierarchy of hematopoiesis

“…There are approximately $1.0 Â 10 5 CFU-GEMM cells [30] and significantly more CFU-GM cells ($10 8 ). We estimate that each CFU-GEMM may contribute to hematopoiesis for an average of $60 days (range 40-340 days), and that it replicates at an average rate of once every 50 days (range 35-285 days), while the replication rate of CFU-GM is significantly faster [21].…”