Library
local_library Home Repository

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

Journal Article (2025)
Author(s)

Daisong Wang (University Medical Center Utrecht, Koninklijke Nederlandse Akademie van Wetenschappen (KNAW))

Willem Kasper Spoelstra (AMOLF Institute for Atomic and Molecular Physics)

Lin Lin (Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Center Utrecht)

Ninouk Akkerman (Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Center Utrecht)

Daniel Krueger (University Medical Center Utrecht, Koninklijke Nederlandse Akademie van Wetenschappen (KNAW))

Talya Dayton (Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Center Utrecht)

Jeroen S. van Zon (AMOLF Institute for Atomic and Molecular Physics)

Sander J. Tans (Kavli institute of nanoscience Delft, AMOLF Institute for Atomic and Molecular Physics, TU Delft - BN/Sander Tans Lab)

Johan H. van Es (University Medical Center Utrecht, Koninklijke Nederlandse Akademie van Wetenschappen (KNAW))

Hans Clevers (University Medical Center Utrecht, Koninklijke Nederlandse Akademie van Wetenschappen (KNAW))

Research Group
BN/Sander Tans Lab
DOI related publication
https://doi.org/10.1016/j.stem.2025.02.003
More Info
expand_more
Publication Year
2025
Language
English
Research Group
BN/Sander Tans Lab
Issue number
4
Volume number
32
Pages (from-to)
598-612.e5
Reuse Rights

Other than for strictly personal use, it is not permitted to download, forward or distribute the text or part of it, without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license such as Creative Commons.

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.