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The origin of hematopoietic cell type diversity

Oncogene volume 23, pages 7188–7198 (2004)Cite this article

Abstract

The hematopoietic system remains robust with regards to extrinsic perturbations, in sharp contrast with the stochastic behavior of hematopoeitic stem cells (HSCs) at the single cell level, suggesting that stability may be achieved within a stem cell system that undergoes constant self-renewal, commitment to differentiation and generates cell type diversification. Converging evidence at the interface of cellular, molecular and numerical studies suggests that diversity is generated by the chaotic dynamics of transcription factor networks within a cell and of the combination of growth factors and cytokines in the environment, both involving cooperation and competition. Current evidence indicates that HSCs are primed for multilineage gene expression. A subtle shift in transcription factor dosage is sufficient to perturb this equilibrium and to drive lineage commitment that involves a resolution of complexity at the molecular level and a transition towards less chaotic behavior. This dynamical instability establishes a state of responsiveness to extrinsic signals. Evolutionary conserved environmental cues that drive pattern formation or migratory behavior during embryonic development operate in the adult to influence the decision between self-renewal and differentiation in HSCs, as exemplified by the role of Notch1, Wnt proteins, BMPs and VEGF. In contrast, a network of cytokines uniquely present in mammalians influences later developmental stages, from progenitors with more restricted potentials (tri-, bi- or unipotent) to mature functional cells. These cytokines have co-opted the ancient Jak-STAT pathway but also appear to trigger lineage-affiliated transcription factors, thus linking environmental signaling to cell fate decisions.

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Acknowledgements

We thanks all members of the laboratory, colleagues and collaborators for stimulating discussions, and the Canadian Institutes of Health Research, the National Cancer Institute of Canada, the Leukemia Research Fund of Canada, the Cancer Research Society and the Canada Research Chairs.

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  1. Institute of Immunology and Cancer, University of Montréal, Montréal, H3C 3J7, Québec, Canada

    Trang Hoang

  2. Department of Pharmacology, University of Montréal, Montréal, H3C 3J7, Québec, Canada

    Trang Hoang

  3. Department of Biochemistry, University of Montréal, Montréal, H3C 3J7, Québec, Canada

    Trang Hoang

  4. Department of Molecular Biology, University of Montréal, Montréal, H3C 3J7, Québec, Canada

    Trang Hoang

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Correspondence to Trang Hoang.

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Dynamical systems are not analysed in real space but in a multidimensional phase space that depends on the number of variables describing the system. Chaotic systems eventually settle on a structure of lower dimension than their phase space, called the strange attractor.

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Hoang, T. The origin of hematopoietic cell type diversity. Oncogene 23, 7188–7198 (2004). https://doi.org/10.1038/sj.onc.1207937

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