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Abstract: TH-PO533

Human Scattered Tubular Cells Represent a Heterogeneous Population of Glycolytic Dedifferentiated Proximal Tubule Cells

Session Information

  • Pathology and Lab Medicine
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

  • 1700 Pathology and Lab Medicine

Authors

  • van den Broek, Martijn, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, Netherlands
  • Eymael, Jennifer, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, Netherlands
  • Miesen, Laura, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, Netherlands
  • Villacorta Monge, Valerie Josephina, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, Netherlands
  • van den Berge, Bartholomeus Tideman, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, Netherlands
  • Mooren, Fieke, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, Netherlands
  • Hermsen, Meyke, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, Netherlands
  • Bándi, Péter, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, Netherlands
  • Willemsen, Brigith, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, Netherlands
  • Florquin, Sandrine, Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
  • Wetzels, Roy, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, Netherlands
  • Kramann, Rafael, Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
  • Wetzels, Jack F., Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, Netherlands
  • Jansen, Jitske, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, Netherlands
  • Smeets, Bart, Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, Netherlands

Group or Team Name

  • Smeetslab
Background

Scattered tubular cells (STCs) are a phenotypically distinct cell population in the proximal tubule that increase in number after acute kidney injury. Since much of our knowledge about STCs comes from animal experiments, we aimed to characterize the human STC population.

Methods

3D tissue analysis was performed on consecutive immunostained kidney slides. The percentage of STCs was determined using immunofluorescent staining for aquaporin-1 to detect proximal tubule epithelial cells (PTECs) and phosphofructokinase-platelet (PFKP) to detect STCs. STC (CD13+CD24+CD133+) and PTEC (CD13+CD24-CD133-) cells were sorted (FACS) from 5 seperate normal nephrectomy samples. Sorted cells were used as input for bulk RNA sequencing.

Results

3D tissue analysis revealed that STCs prefer to locate in the sharp inner bends of the tubule in groups rather than as single cells. STCs are barely present in young kidney tissue (<2 years) and their number significantly increases with age. Also, we observed an increased number of STCs with increased acute tubular injury (KIM-1) as well as interstitial fibrosis (a-SMA). RNA bulk sequencing revealed an upregulation of NFκB, TNFα and other inflammatory pathways in STCs, whereas normal proximal tubular function, metabolism and especially the TCA cycle and oxidative phosphorylation were downregulated. Histologically, we confirmed a glycolytic isoform switch in STCs from pyruvate kinase-Liver (PKL) to PK-Muscle 2 (PKM2) and from PFKL to PFKP. The transcriptome of STCs did not show signs of cellular senescence, confirmed by immunostaining for p53, p16 and lamin B1. Immunostaining and a single-cell RNA sequencing database showed that STCs are in a transient state representing a heterogeneous population with different marker expression, ligand-receptor interactions and pathway activity.

Conclusion

Human STCs represent a heterogeneous population of dedifferentiated PTECs showing a metabolic shift towards glycolysis, which could facilitate cellular survival after kidney injury.