Intercellular network structure and regulatory motifs in the human hematopoietic system

Molecular Systems Biology

Wenlian Qiao¹  Weijia Wang¹  Elisa Laurenti³  Andrei L Turinsky²  Shoshana J Wodak²  Gary D Bader⁴  John E Dick³ 

[1] Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada;The Hospital for Sick Children, Toronto, ON, Canada;Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada;Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

关键词: feedback regulation;    hematopoietic stem cell;    intercellular signaling;   

DOI  :  10.15252/msb.20145141

来源: Wiley

【 摘 要 】

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.

Synopsis

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.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.