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Mol Syst Biol. 2014 Jul 15;10:741. doi: 10.15252/msb.20145141.

Intercellular network structure and regulatory motifs in the human hematopoietic system.

Author information

1
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
2
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
3
The Hospital for Sick Children, Toronto, ON, Canada.
4
The Hospital for Sick Children, Toronto, ON, Canada Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
5
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada Department of Computer Science, University of Toronto, Toronto, ON, Canada The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
6
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada The Donnelly Centre, University of Toronto, Toronto, ON, Canada Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada McEwen Centre for Regenerative Medicine, University of Health Network, Toronto, ON, Canada Heart & Stroke/Richard Lewar Centre of Excellence, Toronto, ON, Canada peter.zandstra@utoronto.ca.

Abstract

The hematopoietic system is a distributed tissue that consists of functionally distinct cell types continuously produced through hematopoietic stem cell (HSC) differentiation. Combining genomic and phenotypic data with high-content experiments, we have built a directional cell-cell communication network between 12 cell types isolated from human umbilical cord blood. Network structure analysis revealed that ligand production is cell type dependent, whereas ligand binding is promiscuous. Consequently, additional control strategies such as cell frequency modulation and compartmentalization were needed to achieve specificity in HSC fate regulation. Incorporating the in vitro effects (quiescence, self-renewal, proliferation, or differentiation) of 27 HSC binding ligands into the topology of the cell-cell communication network allowed coding of cell type-dependent feedback regulation of HSC fate. Pathway enrichment analysis identified intracellular regulatory motifs enriched in these cell type- and ligand-coupled responses. This study uncovers cellular mechanisms of hematopoietic cell feedback in HSC fate regulation, provides insight into the design principles of the human hematopoietic system, and serves as a foundation for the analysis of intercellular regulation in multicellular systems.

KEYWORDS:

feedback regulation; hematopoietic stem cell; intercellular signaling

PMID:
25028490
PMCID:
PMC4299490
[Indexed for MEDLINE]
Free PMC Article

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