The transcriptional and regulatory identity of erythropoietin producing cells

Bjørt K. Kragesteen*, Amir Giladi, Eyal David, Shahar Halevi, Laufey Geirsdóttir, Olga M. Lempke, Baoguo Li, Andreas M. Bapst, Ken Xie, Yonatan Katzenelenbogen, Sophie L. Dahl, Fadi Sheban, Anna Gurevich-Shapiro, Mor Zada, Truong San Phan, Roberto Avellino, Shuang Yin Wang, Oren Barboy, Shir Shlomi-Loubaton, Sandra WinningPhilipp P. Markwerth, Snir Dekalo, Hadas Keren-Shaul, Merav Kedmi, Martin Sikora, Joachim Fandrey, Thorfinn S. Korneliussen, Josef T. Prchal, Barak Rosenzweig, Vladimir Yutkin, Fernando Racimo, Eske Willerslev, Chamutal Gur, Roland H. Wenger, Ido Amit*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1191-1200
Number of pages10
JournalNature Medicine
Volume29
Issue number5
DOIs
StatePublished - May 2023

Funding

FundersFunder number
European Union European Research Council101055341-TROJAN-Cell
ISF Israel Precision Medicine Program607/20
European Molecular Biology OrganizationALTF 112-2022
Villum Fonden00025300
Human Frontier Science ProgramLT 000230/2019
Deutsche Forschungsgemeinschaft259373024 – TRR 167
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung310030_184813 R.H.W.
Israel Science Foundation1944/22

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