Intercellular network structure and regulatory motifs in the human hematopoietic system
Article first published online: 15 JUL 2014
© 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Molecular Systems Biology
Volume 10, Issue 7, July 2014
How to Cite
Mol Syst Biol. (2014) 10: 741
- Issue published online: 1 JUL 2014
- Article first published online: 15 JUL 2014
- Manuscript Accepted: 17 JUN 2014
- Manuscript Revised: 9 JUN 2014
- Manuscript Received: 20 JAN 2014
- Swiss National Science Foundation
- Foundation Suisse pour les Bourses en Médecine et Biologie (FSBMB)
- Canadian Institutes of Health Research
- Ontario Research Fund
- SickKids Foundation
- NRNB. Grant Number: P41 GM103504
- Genome Canada through the Ontario Genomics Institute
- Ontario Institute for Cancer Research
- Canadian Institutes for Health Research, a Canada Research Chair
- Princess Margaret Hospital Foundation
- Terry Fox Research Institute
- Canadian Cancer Society Research Institute
- Ontario Ministry of Health and Long Term Care (OMOHLTC)
- Leukemia and Lymphoma Society of Canada
- Canadian Stem Cell Network
- Ministry of Research and Innovation of Ontario
- feedback regulation;
- hematopoietic stem cell;
- intercellular signaling
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.
A directional cell-cell communication network of human hematopoietic cells reveals mechanisms of hematopoietic cell feedback in HSC fate regulation and provides insight into the design principles of the human hematopoietic system.
- Ligand production by hematopoietic cells is cell type-dependent, whereas ligand binding is promiscuous.
- Cell frequency modulation and compartmentalization establish specificity in HSC fate regulation.
- Differentiated blood cells influence HSC fate through cell type-specific feedback signals.
- Pathway analysis identifies intracellular pathway nodes enriched in cell type and ligand coupled responses.