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

Ingmar Glauche, Michael Cross, Markus Loeffler, Ingo Roeder
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
Stem Cells 25(7), pages 1791--1799, July 2007
@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 }}