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A unified workflow to define multipotent progenitor hierarchies (TEA-Seq)

ABSTRACT: Multipotent hematopoietic progenitors with coherent developmental transcriptional programs are defined by their ability to give rise to distinct cell lineages. While the identification of multilineage progenitors is aided by single-cell technologies, new techniques are required for their rigorous delineation and isolation. We describe a new approach to dissect and contrast well-defined and newly proposed immunophenotypically defined hematopoietic progenitors using integrative multimodal single-cell genomics and linked high-dimensional flow cytometry. The lineage potential of implicated multi-lineage progenitors could be resolved through their sequential isolation, lineage tracing, genetic reporters, in vitro differentiation and gene-regulatory prediction analyses. These analyses implicate coordinated transcription factors operating on composite elements for distinct multilineage cell states. A newly identified precursor of the neutrophil-monocytic bipotential (MultiLin-1) was confirmed to be transcriptionally reprogrammed by Th2 cytokines following infection, to produce the successive waves of neutrophils, basophils and eosinophils. This work supports a stepwise model of hematopoiesis in which lineage transitions occur as discrete, isolatable cell states.

ORGANISM(S): Mus musculus

PROVIDER: GSE266524 | GEO | 2025/10/21

REPOSITORIES: GEO

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Project description:During development, stem and progenitor cells divide and transition through germ layer- and lineage-specific multipotent states to generate the diverse cell types that compose an animal. Defined changes in biomolecular composition underlie the progressive loss of potency and acquisition of lineage-specific characteristics. For example, multipotent cardiopharyngeal progenitors display multilineage transcriptional priming, whereby both the cardiac and pharyngeal muscle programs are partially active and coexist in the same progenitor cells, while their daughter cells engage in a cardiac or pharyngeal muscle differentiation path only after cell division. Here, using the tunicate Ciona, we studied the acquisition of multilineage competence and the coupling between fate decisions and cell cycle progression. We showed that multipotent cardiopharyngeal progenitors acquire the competence to produce distinct Tbx1/10 (+) and (-) daughter cells shortly before mitosis, which is necessary for Tbx1/10 activation. By combining transgene-based sample barcoding with single cell RNA-seq (scRNA-seq), we uncovered transcriptome-wide dynamics in migrating cardiopharyngeal progenitors as cells progress through G1, S and G2 phases. We termed this process “transcriptome maturation”, and identified candidate “mature genes”, including the Rho GAP-coding gene Depdc1, which peak in late G2. Functional assays indicated that transcriptome maturation fosters cardiopharyngeal competence, in part through multilineage priming and proper oriented and asymmetric division that influences subsequent fate decisions, illustrating the concept of “behavioral competence”. Both classic feedforward circuits and coupling with cell cycle progression drive transcriptome maturation, uncovering distinct levels of coupling between cell cycle progression and fateful molecular transitions. We propose that coupling competence and fate decision with the G2 and G1 phases, respectively, ensures the timely deployment of lineage-specific programs.

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A unified workflow to define multipotent progenitor hierarchies (TEA-Seq)

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