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.
Highlights
The hematopoietic system is a distributed tissue consisting of multiple phenotypically and functionally distinct cell types
Stem and progenitor cells, except for megakaryocyte–erythroid progenitors (MEP), over-expressed hematopoietic stem cell (HSC) proliferation and differentiation genes; MEP and erythroblasts (EryB) over-expressed erythrocyte and megakaryocyte (Mega) differentiation genes; monocytes (Mono) over-expressed genes related to leukocyte and neutrophil (Neut) biological properties; and precursor B cells (PreB) over-expressed genes related to PreB differentiation
We found that the CCC network can be depicted in two formats based on signal directionality— ligand production and ligand binding, and each format was analyzed as an individual network
Summary
The hematopoietic system is a distributed tissue consisting of multiple phenotypically and functionally distinct cell types. Increasing evidence suggests that HSC fate decisions are regulated in part via feedback mechanisms including HSC autocrine signaling and paracrine signaling from differentiated hematopoietic cells (Csaszar et al, 2012; Heazlewood et al, 2013). The key signaling molecules and cell types involved and how multiple often competing feedback signals act to regulate HSC fate in a coordinated manner are poorly understood. We identified lineage-dependent stimulatory and inhibitory signals that constitute a dynamic and complex feedback signaling network for hematopoietic stem and progenitor cell (HSPC) proliferation. This led to the development of an effective culture system capable of expanding human UCB HSC by globally diluting inhibitory feedback signals (Csaszar et al, 2012), pointing to the relevance of the network that our modeling approach uncovered. How the feedback signaling network is organized and how HSCs sense and interpret the signals produced by different cell types remains to be elucidated
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