title: Intercellular network structure and regulatory motifs in the human hematopoietic system.
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.
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
authors.forename: Wenlian
authors.initials: W
authors.lastname: Qiao
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
authors.forename: Weijia
authors.initials: W
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Elisa
authors.initials: E
authors.lastname: Laurenti
authors.affiliation: The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Turinsky
authors.affiliation: The Hospital for Sick Children, Toronto, ON, Canada Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
authors.forename: Shoshana J
authors.initials: SJ
authors.lastname: Wodak
authors.affiliation: 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.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.affiliation: 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.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Zandstra
mesh_terms: D000465:Algorithms; D002450:Cell Communication; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D008024:Ligands
chemical_list: D008024:Ligands
keywords: feedback regulation; hematopoietic stem cell; intercellular signaling