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First published online April 5, 2007
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2007-0025v1
25/7/1791    most recent
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Submitted on January 10, 2007
Accepted on March 28, 2007

Tissue-Specific Stem Cells

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

Ingmar Glauche 1*, Michael Cross 2, Markus Loeffler 1, Ingo Roeder 1

1 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
2 Division of Hematology/Oncology, IZKF, University of Leipzig, Leipzig, Germany

* To whom correspondence should be addressed. E-mail: ingmar.glauche{at}imise.uni-leipzig.de.


  Abstract

Lineage specification of hematopoietic stem cells is considered as a progressive restriction in lineage potential. This view is consistent with observations that differentiation and lineage specification is preceded by a low-level co-expression of lineage specific, potentially antagonistic genes in early progenitor cells. This co-existence, commonly referred to as priming, disappears in the course of differentiation when certain lineage restricted genes are up-regulated while others are down-regulated.

Based on this phenomenological description, we propose a quantitative model which 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 co-expression 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.

 Key Words. lineage specification, hematopoiesis, stem cells, mathematical model, simulation, systems biology




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I. Roeder, K. Horn, H.-B. Sieburg, R. Cho, C. Muller-Sieburg, and M. Loeffler
Characterization and quantification of clonal heterogeneity among hematopoietic stem cells: a model-based approach
Blood, December 15, 2008; 112(13): 4874 - 4883.
[Abstract] [Full Text] [PDF]


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