Interferon-responsive intestinal BEST4/CA7+ cells are targets of bacterial diarrheal toxins
Daisong Wang (Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Centre Utrecht)
Willem Kasper Spoelstra (AMOLF Institute for Atomic and Molecular Physics)
Lin Lin ( University Medical Centre Utrecht, Koninklijke Nederlandse Akademie van Wetenschappen (KNAW))
Ninouk Akkerman (Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Centre Utrecht)
Daniel Krueger (Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Centre Utrecht)
Talya Dayton (Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Centre 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 (Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Centre Utrecht)
Hans Clevers (Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Centre Utrecht)
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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.
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