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 Winning; Philipp 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

doi:10.1038/s41591-023-02314-7

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 af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

33 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature Medicine
Vol/bind	29
Udgave nummer	5
Sider (fra-til)	1191-1200
ISSN	1078-8956
DOI	https://doi.org/10.1038/s41591-023-02314-7
Status	Udgivet - 2023

Bibliografisk note

Funding Information:
We thank members of the Amit laboratory for critical discussions. We thank Y. Kuperman, L. Adler and S. Viukov for assisting with hypoxia experiments. We thank K. Pozyuchenko, G.H. Siloni, C. Padberg and T. Bajanowski for assisting with human kidney samples, and P. Spielmann and T. Knöpfel for technical support. We thank T.-M. Salame, E. Hagai and E. Kopitman for assisting with flow cytometry. This study was funded by European Union European Research Council Advanced (grant no. 101055341-TROJAN-Cell, I.A.); Deutsche Forschungsgemeinschaft (Project-ID 259373024 – TRR 167, I.A.), Israel Science Foundation (ISF; grant no. 1944/22, I.A.), the ISF Israel Precision Medicine Program (607/20, I.A.), Human Frontier Science Program (long-term postdoctoral fellow LT 000230/2019, B.K.K.), European Molecular Biology Organization (postdoctoral fellowship, ALTF 112-2022, A.G.), Villum Fonden (Young Investigator award project no. 00025300, F.R.) and by the Swiss National Science Foundation (grant no. 310030_184813 R.H.W.).

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

Adgang til dokumentet

10.1038/s41591-023-02314-7

Citationsformater

Kragesteen, B. K., Giladi, A., David, E., Halevi, S., Geirsdóttir, L., Lempke, O. M., Li, B., Bapst, A. M., Xie, K., Katzenelenbogen, Y., Dahl, S. L., Sheban, F., Gurevich-Shapiro, A., Zada, M., Phan, T. S., Avellino, R., Wang, S.-Y., Barboy, O., Shlomi-Loubaton, S., ... Amit, I. (2023). The transcriptional and regulatory identity of erythropoietin producing cells. Nature Medicine, 29(5), 1191-1200. https://doi.org/10.1038/s41591-023-02314-7

Kragesteen, BK, Giladi, A, David, E, Halevi, S, Geirsdóttir, L, Lempke, OM, Li, B, Bapst, AM, Xie, K, Katzenelenbogen, Y, Dahl, SL, Sheban, F, Gurevich-Shapiro, A, Zada, M, Phan, TS, Avellino, R, Wang, S-Y, Barboy, O, Shlomi-Loubaton, S, Winning, S, Markwerth, PP, Dekalo, S, Keren-Shaul, H, Kedmi, M, Sikora, M, Fandrey, J, Korneliussen, TS, Prchal, JT, Rosenzweig, B, Yutkin, V, Racimo, F , Willerslev, E, Gur, C, Wenger, RH & Amit, I 2023, 'The transcriptional and regulatory identity of erythropoietin producing cells', Nature Medicine, bind 29, nr. 5, s. 1191-1200. https://doi.org/10.1038/s41591-023-02314-7

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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.",

author = "Kragesteen, {Bj{\o}rt K.} and Amir Giladi and Eyal David and Shahar Halevi and Laufey Geirsd{\'o}ttir and Lempke, {Olga M.} and Baoguo Li and Bapst, {Andreas M.} and Ken Xie and Yonatan Katzenelenbogen and Dahl, {Sophie L.} and Fadi Sheban and Anna Gurevich-Shapiro and Mor Zada and Phan, {Truong San} and Roberto Avellino and Shuang-Yin Wang and Oren Barboy and Shir Shlomi-Loubaton and Sandra Winning and Markwerth, {Philipp P.} and Snir Dekalo and Hadas Keren-Shaul and Merav Kedmi and Martin Sikora and Joachim Fandrey and Korneliussen, {Thorfinn S.} and Prchal, {Josef T.} and Barak Rosenzweig and Vladimir Yutkin and Fernando Racimo and Eske Willerslev and Chamutal Gur and Wenger, {Roland H.} and Ido Amit",

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AU - Kragesteen, Bjørt K.

AU - Giladi, Amir

AU - David, Eyal

AU - Halevi, Shahar

AU - Geirsdóttir, Laufey

AU - Lempke, Olga M.

AU - Li, Baoguo

AU - Bapst, Andreas M.

AU - Xie, Ken

AU - Katzenelenbogen, Yonatan

AU - Dahl, Sophie L.

AU - Sheban, Fadi

AU - Gurevich-Shapiro, Anna

AU - Zada, Mor

AU - Phan, Truong San

AU - Avellino, Roberto

AU - Wang, Shuang-Yin

AU - Barboy, Oren

AU - Shlomi-Loubaton, Shir

AU - Winning, Sandra

AU - Markwerth, Philipp P.

AU - Dekalo, Snir

AU - Keren-Shaul, Hadas

AU - Kedmi, Merav

AU - Sikora, Martin

AU - Fandrey, Joachim

AU - Korneliussen, Thorfinn S.

AU - Prchal, Josef T.

AU - Rosenzweig, Barak

AU - Yutkin, Vladimir

AU - Racimo, Fernando

AU - Willerslev, Eske

AU - Gur, Chamutal

AU - Wenger, Roland H.

AU - Amit, Ido

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

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DO - 10.1038/s41591-023-02314-7

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SN - 1078-8956

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