Erythropoietin directly remodels the clonal composition of murine hematopoietic multipotent progenitor cells
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Curated by eLife
Evaluation Summary:
This paper will be of broad interest to readers in the field of cytokine signaling, experimental hematology and clinical hematology. Erythropoietin is one of the most widely used cytokines clinically but the cells it exerts its effects on has been debated. This study has combined clonal lineage tracing and single cell sequencing to understand the cell population that responds to erythropoietin and indicates that erythropoietin acts directly on multipotent progenitors to transiently modulate their output.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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Abstract
The cytokine erythropoietin (EPO) is a potent inducer of erythrocyte development and one of the most prescribed biopharmaceuticals. The action of EPO on erythroid progenitor cells is well established, but its direct action on hematopoietic stem and progenitor cells (HSPCs) is still debated. Here, using cellular barcoding, we traced the differentiation of hundreds of single murine HSPCs, after ex vivo EPO exposure and transplantation, in five different hematopoietic cell lineages, and observed the transient occurrence of high-output myeloid-erythroid-megakaryocyte-biased and myeloid-B-cell-dendritic cell-biased clones. Single-cell RNA sequencing analysis of ex vivo EPO-exposed HSPCs revealed that EPO induced the upregulation of erythroid associated genes in a subset of HSPCs, overlapping with multipotent progenitor (MPP) 1 and MPP2. Transplantation of barcoded EPO-exposed MPP2 confirmed their enrichment in myeloid-erythroid-biased clones. Collectively, our data show that EPO does act directly on MPP independent of the niche and modulates fate by remodeling the clonal composition of the MPP pool.
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Joint Public Review:
Eisele et al. evaluated the direct action of erythropoietin (EPO) on hematopoietic stem and progenitor cells that included hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs). They used cellular barcoding to enable in vivo tracking of cellular output and then used scRNA-seq to corroborate their findings. They observed the transiently promoted output of Myeloid-Erythroid (ME)-biased and Myeloid-B-cell (MB)-biased clones. Single-cell RNA sequencing analysis revealed that EPO acted mostly on MPP1 and MPP2. Based on these data, the authors concluded that EPO acts directly on MPPs and transiently modulates their output. Although the conceptual advance brought by this study is incremental as similar findings have been presented by previous studies, the integration and use of both barcoding and scRNA-seq …
Joint Public Review:
Eisele et al. evaluated the direct action of erythropoietin (EPO) on hematopoietic stem and progenitor cells that included hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs). They used cellular barcoding to enable in vivo tracking of cellular output and then used scRNA-seq to corroborate their findings. They observed the transiently promoted output of Myeloid-Erythroid (ME)-biased and Myeloid-B-cell (MB)-biased clones. Single-cell RNA sequencing analysis revealed that EPO acted mostly on MPP1 and MPP2. Based on these data, the authors concluded that EPO acts directly on MPPs and transiently modulates their output. Although the conceptual advance brought by this study is incremental as similar findings have been presented by previous studies, the integration and use of both barcoding and scRNA-seq adds strength to the conclusions reached in the present study.
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Evaluation Summary:
This paper will be of broad interest to readers in the field of cytokine signaling, experimental hematology and clinical hematology. Erythropoietin is one of the most widely used cytokines clinically but the cells it exerts its effects on has been debated. This study has combined clonal lineage tracing and single cell sequencing to understand the cell population that responds to erythropoietin and indicates that erythropoietin acts directly on multipotent progenitors to transiently modulate their output.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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