The transcriptional and regulatory identity of erythropoietin producing cells

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. Single-cell analyses in a reporter mouse model and human tissues identify a rare cell subset that produces erythropoietin in vivo, opening potential new avenues for research in erythropoiesis and oxygen homeostasis.

Automated summary

Single-cell RNA and transposase-accessible chromatin (ATAC) sequencing in a mouse model identified a rare cell subset called Norn cells in kidney stroma as the major source of endocrine Epo production in mice, and this finding was confirmed in human kidney tissues. These findings provide new insights into EPO gene regulation and may lead to improved therapies for anemia.