Lineage tracing reveals transient phenotypic adaptation of tubular cells during acute kidney injury

Marc Buse; Mingbo Cheng; Vera Jankowski; Michaela Lellig; Viktor Sterzer; Thiago Strieder; Katja Leuchtle; Ina V Martin; Claudia Seikrit; Paul Brinkkoettter; Giuliano Crispatzu; Jürgen Floege; Peter Boor; Timotheus Speer; Rafael Kramann; Tammo Ostendorf; Marcus J Moeller; Ivan G Costa; Eleni Stamellou

doi:10.1016/j.isci.2024.109255

Lineage tracing reveals transient phenotypic adaptation of tubular cells during acute kidney injury

iScience. 2024 Feb 16;27(3):109255. doi: 10.1016/j.isci.2024.109255. eCollection 2024 Mar 15.

Authors

Marc Buse¹, Mingbo Cheng², Vera Jankowski³, Michaela Lellig³, Viktor Sterzer¹, Thiago Strieder¹, Katja Leuchtle¹, Ina V Martin¹, Claudia Seikrit¹, Paul Brinkkoettter⁴, Giuliano Crispatzu⁴, Jürgen Floege¹, Peter Boor^{1

5}, Timotheus Speer⁶, Rafael Kramann^{1

7

8}, Tammo Ostendorf¹, Marcus J Moeller¹, Ivan G Costa², Eleni Stamellou¹

Affiliations

¹ Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
² Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany.
³ Institute for Molecular Cardiovascular Research, RWTH Aachen University Hospital, Aachen, Germany.
⁴ Department II of Internal Medicine and Centre for Molecular Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
⁵ Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
⁶ Medical Clinic 4, Nephrology, University of Frankfurt und Goethe-University Frankfurt, Frankfurt am Main, Germany.
⁷ Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.
⁸ Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, the Netherlands.

Abstract

Tubular injury is the hallmark of acute kidney injury (AKI) with a tremendous impact on patients and health-care systems. During injury, any differentiated proximal tubular cell (PT) may transition into a specific injured phenotype, so-called "scattered tubular cell" (STC)-phenotype. To understand the fate of this specific phenotype, we generated transgenic mice allowing inducible, reversible, and irreversible tagging of these cells in a murine AKI model, the unilateral ischemia-reperfusion injury (IRI). For lineage tracing, we analyzed the kidneys using single-cell profiling during disease development at various time points. Labeled cells, which we defined by established endogenous markers, already appeared 8 h after injury and showed a distinct expression set of genes. We show that STCs re-differentiate back into fully differentiated PTs upon the resolution of the injury. In summary, we show the dynamics of the phenotypic transition of PTs during injury, revealing a reversible transcriptional program as an adaptive response during disease.

Keywords: Cell biology; Nephrology.