Lineage Specification of Hematopoietic Stem Cells: Mathematical Modeling and Biological Implications


Ingmar Glauche, Michael Cross, Markus Loeffler, Ingo Roeder

Stem Cells 25(7), pages 17911799, July 2007

Lineage specification of hematopoietic stem cells is considered a progressive restriction in lineage potential. This view is consistent with observations that differentiation and lineage specification is preceded by a low-level coexpression of lineage specific, potentially antagonistic genes in early progenitor cells. This coexistence, commonly referred to as priming, disappears in the course of differentiation when certain lineage-restricted genes are upregulated while others are downregulated. Based on this phenomenological description, we propose a quantitative model that describes lineage specification as a competition process between different interacting lineage propensities. The competition is governed by environmental stimuli promoting a drift from a multipotent coexpression to the dominance of one lineage. The assumption of a context-dependent intracellular differentiation control is consistently embedded into our previously proposed model of hematopoietic stem cell organization. The extended model, which comprises self-renewal and lineage specification, is verified using available data on the lineage specification potential of primary hematopoietic stem cells and on the differentiation kinetics of the FDCP-mix cell line. The model provides a number of experimentally testable predictions. From our results, we conclude that lineage specification is best described as a flexible and temporally extended process in which lineage commitment emerges as the result of a sequence of small decision steps. The proposed model provides a novel systems biological view on the functioning of lineage specification in adult tissue stem cells and its connections to the self-renewal properties of these cells.

(keywords)  Lineage specification, Hematopoiesis, Stem cells, Mathematical model, Simulation, Systems biology
 @article{hscmodel-stemcells07,
volume = 25,
title = {Lineage Specification of Hematopoietic Stem Cells: Mathematical Modeling and Biological Implications},
number = 7,
url-pdf = {http://stemcells.alphamedpress.org/cgi/reprint/25/7/1791.pdf},
month = {July},
doi = {10.1634/stemcells.2007-0025},
keywords = { Lineage specification, Hematopoiesis, Stem cells, Mathematical model, Simulation, Systems biology},
status = {Published},
year = 2007,
pages = {1791--1799},
journal = {Stem Cells},
author = {Glauche, Ingmar and Cross, Michael and Loeffler, Markus and Roeder, Ingo }

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Ingmar Glauche, Michael Cross, Markus Loeffler, Ingo Roeder

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published

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Stem Cells

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25

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7

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17911799

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July 2007

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10.1634/stemcells.2007-0025

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hscmodel-stemcells07
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