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Xenotransplanted human organoids identify transepithelial zinc transport as a key mediator of intestinal adaptation

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Listed:
  • Maame Efua S. Sampah

    (Johns Hopkins University School of Medicine
    Johns Hopkins Hospital)

  • Hannah Moore

    (Johns Hopkins University School of Medicine)

  • Raheel Ahmad

    (Johns Hopkins University School of Medicine)

  • Johannes Duess

    (Johns Hopkins University School of Medicine
    Johns Hopkins Hospital)

  • Peng Lu

    (Johns Hopkins University School of Medicine)

  • Carla Lopez

    (Johns Hopkins University School of Medicine
    Johns Hopkins Hospital)

  • Steve Steinway

    (Johns Hopkins University School of Medicine)

  • Daniel Scheese

    (Johns Hopkins University School of Medicine
    Johns Hopkins Hospital)

  • Zachariah Raouf

    (Johns Hopkins University School of Medicine
    Johns Hopkins Hospital)

  • Koichi Tsuboi

    (Johns Hopkins University School of Medicine
    Johns Hopkins Hospital)

  • Jeffrey Ding

    (Johns Hopkins University School of Medicine)

  • Connor Caputo

    (Johns Hopkins University School of Medicine)

  • Madison McFarland

    (Johns Hopkins University School of Medicine)

  • William B. Fulton

    (Johns Hopkins University School of Medicine)

  • Sanxia Wang

    (Johns Hopkins University School of Medicine)

  • Meghan Wang

    (Johns Hopkins University School of Medicine)

  • Thomas Prindle

    (Johns Hopkins University School of Medicine)

  • Vered Gazit

    (Washington University School of Medicine)

  • Deborah C. Rubin

    (Washington University School of Medicine)

  • Samuel Alaish

    (Johns Hopkins University School of Medicine
    Johns Hopkins Hospital)

  • Chhinder P. Sodhi

    (Johns Hopkins University School of Medicine)

  • David J. Hackam

    (Johns Hopkins University School of Medicine
    Johns Hopkins Hospital)

Abstract

Short bowel syndrome (SBS) leads to severe morbidity and mortality. Intestinal adaptation is crucial in improving outcomes. To understand the human gene pathways associated with adaptation, we perform single-cell transcriptomic analysis of human small intestinal organoids explanted from mice with experimental SBS. We show that transmembrane ion pathways, specifically the transepithelial zinc transport pathway genes SLC39A4 and SLC39A5, are upregulated in SBS. This discovery is corroborated by an external dataset, bulk RT-qPCR, and Western blots. Oral zinc supplementation is shown to improve survival and weight gain of SBS mice and increase the proliferation of intestinal crypt cells in vitro. Finally, we identify the upregulation of SLC39A5 and associated transcription factor KLF5 in biopsied intestinal tissue specimens from patients with SBS. Thus, we identify zinc supplementation as a potential therapy for SBS and describe a xenotransplantation model that provides a platform for discovery in other intestinal diseases.

Suggested Citation

  • Maame Efua S. Sampah & Hannah Moore & Raheel Ahmad & Johannes Duess & Peng Lu & Carla Lopez & Steve Steinway & Daniel Scheese & Zachariah Raouf & Koichi Tsuboi & Jeffrey Ding & Connor Caputo & Madison, 2024. "Xenotransplanted human organoids identify transepithelial zinc transport as a key mediator of intestinal adaptation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52216-6
    DOI: 10.1038/s41467-024-52216-6
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    References listed on IDEAS

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    1. Shinya Sugimoto & Eiji Kobayashi & Masayuki Fujii & Yuki Ohta & Kazuya Arai & Mami Matano & Keiko Ishikawa & Kentaro Miyamoto & Kohta Toshimitsu & Sirirat Takahashi & Kosaku Nanki & Yoji Hakamata & Ta, 2021. "An organoid-based organ-repurposing approach to treat short bowel syndrome," Nature, Nature, vol. 592(7852), pages 99-104, April.
    2. Jason R. Spence & Christopher N. Mayhew & Scott A. Rankin & Matthew F. Kuhar & Jefferson E. Vallance & Kathryn Tolle & Elizabeth E. Hoskins & Vladimir V. Kalinichenko & Susanne I. Wells & Aaron M. Zor, 2011. "Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro," Nature, Nature, vol. 470(7332), pages 105-109, February.
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