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.
Highlights
Hematopoiesis is the process for the generation of all cellular blood elements
Blood cell formation has at its root hematopoietic stem cells (HSC) that have the dual property of self renewal and the ability to differentiate into all types of blood cells [1,2,3]
In an adult human,400 HSC [4] are actively contributing to hematopoiesis, replicating at a rate of 1/year [4,5]
Summary
Blood 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. 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. The model agrees with the limited in vivo data available and can make testable predictions.
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