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Keywords:

  • feedback regulation;
  • hematopoietic stem cell;
  • intercellular signaling

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

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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.