2. Academic Validation
  3. Interferon-responsive intestinal BEST4/CA7+ cells are targets of bacterial diarrheal toxins

Interferon-responsive intestinal BEST4/CA7+ cells are targets of bacterial diarrheal toxins

  • Cell Stem Cell. 2025 Feb 24:S1934-5909(25)00042-6. doi: 10.1016/j.stem.2025.02.003.
Daisong Wang 1,  Willem Kasper Spoelstra 2,  Lin Lin 3,  Ninouk Akkerman 1,  Daniel Krueger 1,  Talya Dayton 1,  Jeroen S van Zon 2,  Sander J Tans 4,  Johan H van Es 1,  Hans Clevers 5
Affiliations

Affiliations

  • 1 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht 3584 CT, the Netherlands; Oncode Institute, Hubrecht Institute, Utrecht 3584 CT, the Netherlands.
  • 2 AMOLF, Amsterdam 1009 DB, the Netherlands.
  • 3 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht 3584 CT, the Netherlands; Oncode Institute, Hubrecht Institute, Utrecht 3584 CT, the Netherlands; The Princess Máxima Center for Pediatric Oncology, Utrecht 3584 CS, the Netherlands.
  • 4 AMOLF, Amsterdam 1009 DB, the Netherlands; Department of Bionanoscience, Kavli Institute of Nanoscience Delft, Delft University of Technology, Delft 2629 HZ, the Netherlands.
  • 5 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht 3584 CT, the Netherlands; Oncode Institute, Hubrecht Institute, Utrecht 3584 CT, the Netherlands; The Princess Máxima Center for Pediatric Oncology, Utrecht 3584 CS, the Netherlands. Electronic address: h.clevers@hubrecht.eu.
PMID: 40010349 DOI: 10.1016/j.stem.2025.02.003
Abstract

BEST4/CA7+ cells of the human intestine were recently identified by single-cell RNA Sequencing. While their gene expression profile predicts a role in electrolyte balance, BEST4/CA7+ cell function has not been explored experimentally owing to the absence of BEST4/CA7+ cells in mice and the paucity of human in vitro models. Here, we establish a protocol that allows the emergence of BEST4/CA7+ cells in human intestinal organoids. Differentiation of BEST4/CA7+ cells requires activation of Notch signaling and the transcription factor SPIB. BEST4/CA7+ cell numbers strongly increase in response to the cytokine interferon-γ, supporting a role in immunity. Indeed, we demonstrate that BEST4/CA7+ cells generate robust CFTR-mediated fluid efflux when stimulated with Bacterial diarrhea-causing toxins and find the norepinephrine-ADRA2A axis as a potential mechanism in blocking BEST4/CA7+ cell-mediated fluid secretion. Our observations identify a central role of BEST4/CA7+ cells in fluid homeostasis in response to Bacterial infections.

Keywords

BEST4/CA7(+) cells; bacterial infection; fluid homeostasis; human intestinal organoids; interferon-γ.

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