Single-Cell RNA-Sequencing Reveals a Continuous Spectrum of Differentiation in Hematopoietic Cells

Summary

The transcriptional programs that govern hematopoiesis have been investigated primarily by population-level analysis of hematopoietic stem and progenitor cells, which cannot reveal the continuous nature of the differentiation process. Here we applied single-cell RNA-sequencing to a population of hematopoietic cells in zebrafish as they undergo thrombocyte lineage commitment. By reconstructing their developmental chronology computationally, we were able to place each cell along a continuum from stem cell to mature cell, refining the traditional lineage tree. The progression of cells along this continuum is characterized by a highly coordinated transcriptional program, displaying simultaneous suppression of genes involved in cell proliferation and ribosomal biogenesis as the expression of lineage specific genes increases. Within this program, there is substantial heterogeneity in the expression of the key lineage regulators. Overall, the total number of genes expressed, as well as the total mRNA content of the cell, decreases as the cells undergo lineage commitment.

Graphical Abstract

Highlights

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  Single-cell RNA-sequencing reveals the continuous nature of thrombocyte development

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  Coordinated transcriptional programs govern progression of differentiation

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  Number of genes expressed and mRNA content per cell decrease during differentiation

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  Zebrafish thrombocytes remain transcriptionally active in circulation

Abstract

Computational reconstruction of the thrombocyte’s developmental chronology from scRNA-seq data reveals the continuous nature of the differentiation process. Macaulay et al. show that a highly coordinated transcriptional program characterizes the progression of cells along this continuum. Within this program, there is substantial heterogeneity in the expression of key lineage regulators.