Compartmental Architecture and Dynamics of Hematopoiesis

Abstract

BackgroundBlood cell formation is maintained by the replication of hematopoietic stem cells (HSC) that continuously feed downstream “compartments” where amplification and differentiation of cells occurs, giving rise to all blood lineages. Whereas HSC replicate slowly, committed cells replicate faster as they become more differentiated.Methodology/Significant FindingWe propose a multi-compartment model of hematopoiesis, designed on the principle of cell flow conservation under stationary conditions. Cells lost from one compartment due to differentiation are replaced by cells from the upstream compartment. We assume that there is a constant relationship between cell input and output in each compartment and fix the single parameter of the model using data available for granulocyte maturation. We predict that ∼31 mitotic events separate the HSC from the mature cells observed in the circulation. Besides estimating the number of compartments, our model allows us to estimate the size of each compartment, the rate of cell replication within each compartment, the mean time a given cell type contributes to hematopoiesis, the amplification rate in each compartment, as well as the mean time separating stem-cell replication and mature blood-cell formation.ConclusionsDespite its simplicity, the model agrees with the limited in vivo data available and can make testable predictions. In particular, our prediction of the average lifetime of a PIG-A mutated clone agrees closely with the experimental results available for the PIG-A gene mutation in healthy adults. The present elucidation of the compartment structure and dynamics of hematopoiesis may prove insightful in further understanding a variety of hematopoietic disorders.

Tyrosine kinase inhibitor therapy can cure chronic myeloid leukemia without hitting leukemic stem cells

“…22 In a healthy adult, approximately 400 hematopoietic stem cells, which each replicate on average once per year, 15,23 are responsible for the daily marrow output of approximately 3.5¥10 11 cells. As cells differentiate, they reach new levels of the hematopoietic tree, and we associate a specific compartment to each stage of cell differentiation (Figure 1).…”

“…Cell divisions contribute to differentiation with a probability ε and to amplification with a probability of 1-ε across the hematopoietic tree. 22 When a cell in compartment i divides and the two daughter cells differentiate they move to the next compartment (i+l). Cells in compartment i replicate at a rate ri that increases exponentially together with compartment size (Nj).…”

“…From prior work, we have determined that there are 32 compartments (K=32) in the hematopoietic tree and that ε=0.85 for normal hematopoiesis. 22 We capture the dynamics of hematopoiesis combining three different approaches including population dynamics in discrete time, age-structured populations and a continuous model when the cell population is large enough. This is similar to cell dynamics in the colonic crypt as described by Johnston et al 24,25 where these approaches are discussed in detail.…”

Modelling Physiological and Pharmacological Control on Cell Proliferation to Optimise Cancer Treatments

“…More generally, stem cells have been studied by probabilistic modelling [68,70,72], by cellular automata [233], by ODEs [192], by difference equations [139] and by PDEs [140] or delay differential equations [183,186], with applications mainly in haematology and haematological diseases (in particular chronic myelogenous leukemia and cyclical neutropenia), where observations of the resulting mature cells populations are easy to perform in the clinic. The interested reader is invited to refer to the rich literature mentioned in the references.…”

“…Stem cells are the pluripotential undifferentiated cells that are found in all renewing tissues, in very small numbers, from which proliferating cell populations arise [266]. They have been particularly studied in the intestinal crypt [221,222] for mucosa proliferation, and in the haematopoietic system [68,69,70,72,139,140,173,192,233]. Stem cells are an object of active research, not only for cancer, but also for other diseases in which tissue reconstruction by young cells is needed.…”