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TISSUE-SPECIFIC STEM CELLS

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

^aInstitute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany;
^bDivision of Hematology/Oncology, Interdisciplinary Center for Clinical Research, University of Leipzig, Leipzig, Germany

Key Words. Lineage specification • Hematopoiesis • Stem cells • Mathematical model • Simulation • Systems biology

Correspondence: Ingmar Glauche, Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Haertelstr. 16/18, 04107 Leipzig, Germany. Telephone: +49 341 97 16 112; Fax: +49 341 97 16 109; e-mail: ingmar.glauche{at}imise.uni-leipzig.de

Received January 10, 2007; accepted for publication March 28, 2007.
First published online in STEM CELLS EXPRESS   April 5, 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.

Disclosure of potential conflicts of interest is found at the end of this article.