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Zebrafish neuromesodermal progenitors undergo a critical state transition in vivo.

ABSTRACT: The transition state model of cell differentiation proposes that a transient window of gene expression stochasticity precedes entry into a differentiated state. Here, we assess this theoretical model in zebrafish neuromesodermal progenitors (NMps) in vivo during late somitogenesis stages. We observed an increase in gene expression variability at the 24 somite stage (24ss) before their differentiation into spinal cord and paraxial mesoderm. Analysis of a published 18ss scRNA-seq dataset showed that the NMp population is noisier than its derivatives. By building in silico composite gene expression maps from image data, we assigned an 'NM index' to in silico NMps based on the expression of neural and mesodermal markers and demonstrated that cell population heterogeneity peaked at 24ss. Further examination revealed cells with gene expression profiles incongruent with their prospective fate. Taken together, our work supports the transition state model within an endogenous cell fate decision making event.

SUBMITTER: Toh K

PROVIDER: S-EPMC9579027 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Zebrafish neuromesodermal progenitors undergo a critical state transition <i>in vivo</i>.

Toh Kane K Saunders Dillan D Verd Berta B Steventon Benjamin B

iScience 20220926 10

The transition state model of cell differentiation proposes that a transient window of gene expression stochasticity precedes entry into a differentiated state. Here, we assess this theoretical model in zebrafish neuromesodermal progenitors (NMps) <i>in vivo</i> during late somitogenesis stages. We observed an increase in gene expression variability at the 24 somite stage (24ss) before their differentiation into spinal cord and paraxial mesoderm. Analysis of a published 18ss scRNA-seq dataset sh ...[more]

PMID: 36274939

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Project description:During commitment of a multipotent stem or progenitor cell to a particular lineage, a large number of genes alter their expression in a coordinated manner orchestrated by the gene regulatory network (GRN). The constraints imposed by the GRN govern how cells move in the high-dimensional gene expression state space and can be understood as a dynamical system in which phenotypic cell states (cell types) are attractors that stabilize the cell-type characteristic gene expression pattern against molecular noise. Despite insights from various theoretical models, it remains elusive how multipotent cells, when committing to a specific lineage, exit their attractor and enter a new distinct attractor. Here we show, using single-cell resolution monitoring of transcript patterns by qPCR that commitment of multipotent blood progenitor cells to either the erythroid or the myeloid lineage is preceded by a destabilization of the progenitorsâ?? attractor state and a slowing-down of relaxation of cells from outlier states, indicating a critical state transition (â??tipping pointâ??). The high-dimensionality of the system (many genes) and availability of individual trajectories of a large ensemble of systems (many cells) affords a novel signature for critical transition which can be predicted from theory: Decrease of correlation between cells and concomitant increase of correlation between genes as the cell population approaches the tipping point. Consistent with a destabilizing bifurcation that simultaneously opens access to the erythroid and myeloid attractors, differentiation signal for either lineage caused some cells to commit to the â??wrongâ?? fate; moreover providing conflicting signals resulted in a delayed decision at the bifurcation point that however was ultimately resolved by commitment to one fate. These results suggest that the theoretical framework of â??early-warning signsâ?? and critical transitions can be applied to ensembles of high-dimensional systems, offering a formal tool for analyzing single-cell omics data beyond current descriptive computational pattern recognition. Mouse blood progenitor cells (EML cell line) was exposed to EPO, IL-3/GM-CSF or a mixture of both cytokines and gene expression change was measured in sorted subpopulations wrt Sca1 progenitor surface marker expression. In total, there was 4 conditions (including control), three time points (including d0) and 20 samples (10 samples in duplicates) were analyzed. Two independent experiments were performed for each condition. The untreated progenitor cell population was used as control.

Dataset Information

Zebrafish neuromesodermal progenitors undergo a critical state transition in vivo.

Publications

Zebrafish neuromesodermal progenitors undergo a critical state transition <i>in vivo</i>.

Similar Datasets

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