Erythropoietin (Epo) is the master regulator of erythropoiesis and oxygen homeostasis. Despite its physiological importance, the molecular and genomic contexts of the cells responsible for renal Epo production remain unclear, limiting more-effective therapies for anemia. Here, we performed single-cell RNA and transposase-accessible chromatin (ATAC) sequencing of an Epo reporter mouse to molecularly identify Epo-producing cells under hypoxic conditions. Our data indicate that a distinct population of kidney stroma, which we term Norn cells, is the major source of endocrine Epo production in mice. We use these datasets to identify the markers, signaling pathways and transcriptional circuits characteristic of Norn cells. Using single-cell RNA sequencing and RNA in situ hybridization in human kidney tissues, we further provide evidence that this cell population is conserved in humans. These preliminary findings open new avenues to functionally dissect EPO gene regulation in health and disease and may serve as groundwork to improve erythropoiesis-stimulating therapies.

促红细胞生成素 (Epo) 是红细胞生成和氧稳态的主要调节剂。尽管其生理学重要性，但负责肾脏 Epo 生成的细胞的分子和基因组背景仍不清楚，这限制了更有效的贫血疗法。在这里，我们对 Epo 报告小鼠进行了单细胞 RNA 和转座酶可及染色质 (ATAC) 测序，以分子鉴定缺氧条件下 Epo 产生细胞。我们的数据表明，一个独特的肾基质群体（我们称之为 Norn 细胞）是小鼠内分泌 Epo 产生的主要来源。我们使用这些数据集来识别 Norn 细胞特征的标记、信号通路和转录电路。利用人肾组织中的单细胞 RNA 测序和 RNA 原位杂交，我们进一步提供证据表明该细胞群在人类中是保守的。这些初步发现为功能剖析开辟了新途径EPO基因在健康和疾病中的调控可能作为改善红细胞生成刺激疗法的基础。