荷兰皇家艺术与科学学院Hans Clevers团队报道了干扰素反应性肠道BEST4/CA7⁺细胞是细菌性腹泻毒素的靶标。这一研究成果发表在2025年2月25日出版的国际学术期刊《细胞—干细胞》上。

该研究组建立了一个允许在人类肠道类器官中出现BEST4/CA7⁺细胞的方案。BEST4/CA7⁺细胞的分化需要激活Notch信号和转录因子SPIB。对细胞因子干扰素-γ的反应中，BEST4/CA7⁺细胞数量强烈增加，支持免疫作用。事实上，课题组证明了BEST4/CA7⁺细胞在受到细菌腹泻导管毒素刺激时产生大量CFTR介导的液体流出，并发现去甲肾上腺素-ADRA2A轴是阻断BEST4/CA7⁺细胞介导的液体分泌的潜在机制。他们的观察确定了BEST4/CA7⁺细胞在应对细菌感染的体液稳态中的核心作用。

研究人员表示，人类肠道的BEST4/CA7⁺细胞最近被单细胞RNA测序鉴定。虽然它们的基因表达谱预测了电解质平衡的作用，但由于小鼠中缺乏BEST4/CA7⁺细胞和缺乏人体外模型，尚未对BEST4/CA7⁺细胞的功能进行实验探索。

附：英文原文

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

Author: Daisong Wang, Willem Kasper Spoelstra, Lin Lin, Ninouk Akkerman, Daniel Krueger, Talya Dayton, Jeroen S. van Zon, Sander J. Tans, Johan H. van Es, Hans Clevers

Issue&Volume: 2025-02-25

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.

DOI: 10.1016/j.stem.2025.02.003

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00042-6