Institut Curie, Université PSL, Sorbonne Université, CNRS UMR168, Laboratoire Physico Chimie Curie, Paris, France.
Netherlands Cancer Institute, Amsterdam, Netherlands.
Elife. 2022 Feb 15;11:e66922. doi: 10.7554/eLife.66922.
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.
细胞因子促红细胞生成素（EPO）是一种强有力的红细胞生成诱导剂，也是最常被开处方的生物制药之一。EPO 对红细胞祖细胞的作用已得到充分证实，但它对造血干细胞和祖细胞（HSPC）的直接作用仍存在争议。在这里，我们使用细胞条形码技术，在五个不同的造血细胞谱系中追踪了数百个经过体外 EPO 暴露和移植的单个鼠 HSPC 的分化情况，并观察到高产量的偏骨髓-红细胞-巨核细胞和偏骨髓-B 细胞-树突状细胞克隆的短暂出现。对体外 EPO 暴露的 HSPC 进行单细胞 RNA 测序分析表明，EPO 在一部分 HSPC 中诱导了与红细胞相关的基因上调，与多能祖细胞（MPP）1 和 MPP2 重叠。移植条形码 EPO 暴露的 MPP2 证实了它们在偏骨髓-红细胞克隆中的富集。总的来说，我们的数据表明，EPO 确实独立于龛位直接作用于 MPP，并通过重塑 MPP 池的克隆组成来调节命运。
