JNK Signalling Regulates Self-Renewal of Proliferative Urine-Derived Renal Progenitor Cells via Inhibition of Ferroptosis

Lisa Nguyen; Leonie Thewes; Michelle Westerhoff; Wasco Wruck; Andreas S Reichert; Carsten Berndt; James Adjaye

doi:10.3390/cells12172197

JNK Signalling Regulates Self-Renewal of Proliferative Urine-Derived Renal Progenitor Cells via Inhibition of Ferroptosis

Cells. 2023 Sep 2;12(17):2197. doi: 10.3390/cells12172197.

Authors

Lisa Nguyen¹, Leonie Thewes², Michelle Westerhoff³, Wasco Wruck¹, Andreas S Reichert³, Carsten Berndt², James Adjaye^{1

4}

Affiliations

¹ Institute of Stem Cell Research and Regenerative Medicine, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
² Department of Neurology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
³ Institute of Biochemistry and Molecular Biology I, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
⁴ EGA Institute for Women's Health, Zayed Centre for Research into Rare Diseases in Children (ZCR), University College London (UCL), 20 Guilford Street, London WC1N 1DZ, UK.

Abstract

With a global increase in chronic kidney disease patients, alternatives to dialysis and organ transplantation are needed. Stem cell-based therapies could be one possibility to treat chronic kidney disease. Here, we used multipotent urine-derived renal progenitor cells (UdRPCs) to study nephrogenesis. UdRPCs treated with the JNK inhibitor-AEG3482 displayed decreased proliferation and downregulated transcription of cell cycle-associated genes as well as the kidney progenitor markers-SIX2, SALL1 and VCAM1. In addition, levels of activated SMAD2/3, which is associated with the maintenance of self-renewal in UdRPCs, were decreased. JNK inhibition resulted in less efficient oxidative phosphorylation and more lipid peroxidation via ferroptosis, an iron-dependent non-apoptotic cell death pathway linked to various forms of kidney disease. Our study is the first to describe the importance of JNK signalling as a link between maintenance of self-renewal and protection against ferroptosis in SIX2-positive renal progenitor cells.

Keywords: JNK signalling; cell death; ferroptosis; mitochondrial metabolism; self-renewal; urine stem cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ferroptosis*
Humans
Kidney
MAP Kinase Signaling System*
Renal Dialysis
Renal Insufficiency, Chronic*
Stem Cells

Grants and funding

J.A. acknowledges the medical faculty of Heinrich Heine University for financial support. J.A., C.B. and A.S.R. acknowledge that this work is partly funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—417677437/GRK2578.