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

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.