Abstract
SummaryThe 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.
Highlights
Hematopoietic stem cells (HSCs) have the ability to self-renew and produce cells that give rise to all different blood cell types (Orkin and Zon, 2008)
Profiling Individual Hematopoietic Cells Ex Vivo Here, we used single-cell RNA-sequencing (RNA-seq) of zebrafish kidney cells to resolve the cellular hierarchy of lineage development in the myeloid branch of hematopoiesis
Inferring Cell States in the Myeloid Lineage To define the identity of cell types within the five clusters, we evaluated the expression of orthologs of transcription factors and other genes known to be relevant in mammalian hematopoiesis, including the expression of early and late markers of megakaryocyte differentiation (Figure 3)
Summary
Hematopoietic stem cells (HSCs) have the ability to self-renew and produce cells that give rise to all different blood cell types (Orkin and Zon, 2008). Our understanding of the functional properties of these various hematopoietic cell types has been advanced mainly by population level analysis. A homogeneous population of cells, as determined by a well-defined set of cell surface markers, may include many functionally distinct populations. This was nicely illustrated in studies showing that within the HSC compartment, individual HSCs may have different reconstitution patterns (e.g., balanced production of myeloid and lymphoid cells or deficiency in lymphoid potential) (Muller-Sieburg et al, 2012). It was demonstrated that common myeloid progenitors (CMP) are a mixed population of cells with distinct lineage potentials (Notta et al, 2015). Single cell transcriptome analysis might provide answers to these outstanding questions (Cvejic, 2015)
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