小柯机器人

美国爱荷华大学John F. Engelhardt等研究人员合作发现，转基因雪貂模型确定肺离子细胞的多样性和功能。相关论文于2023年9月20日在线发表于国际学术期刊《自然》。

研究人员表示，物种分化导致器官细胞生理学的适应性变化，并为研究人类和小鼠之间存在差异的罕见细胞类型功能带来了挑战。人类软骨气道中存在富含囊性纤维化跨膜传导调节因子（CFTR）的稀有肺离子细胞，但小鼠气管近端存在的稀有肺离子细胞数量有限且生物学特性存在差异，因此无法使用传统的转基因模型来阐明气道中离子细胞的功能。

研究人员描述了条件性遗传雪貂模型的创建和使用，通过离子细胞谱系追踪（FOXI1-Cre^ERT2::ROSA-TG）、离子细胞去除（FOXI1-KO）和离子细胞特异性缺失CFTR（FOXI1-Cre^ERT2::CFTR^L/L）来剖析肺离子细胞生物学和功能。通过将这些模型与囊性纤维化雪貂进行比较，研究人员证明离子细胞控制着气道表面液体的吸收、分泌、pH值和粘液粘度，从而导致囊性纤维化、FOXI1-KO和FOXI1-Cre^ERT2::CFTR^L/L雪貂的气道表面液体量减少和粘液纤毛清除受损。这些过程受依赖于CFTR的Cl^-和 HCO₃^-离子转运的调节。单细胞转录组学和体内谱系追踪揭示了气道发育过程中的三种肺离子细胞亚型以及离子细胞、簇细胞和神经内分泌细胞的FOXI1谱系共同稀有细胞祖细胞。因此，稀有肺离子细胞在近端气道中发挥着依赖CFTR的关键功能，而这正是囊性纤维化气道疾病的标志性特征。这些研究为在第一种非啮齿类哺乳动物中使用条件遗传学来研究基因功能、细胞生物学和疾病过程提供了路线图，这些基因功能、细胞生物学和疾病过程在人类和雪貂之间具有更强的演化保守性。

附：英文原文

Title: Transgenic ferret models define pulmonary ionocyte diversity and function

Author: Yuan, Feng, Gasser, Grace N., Lemire, Evan, Montoro, Daniel T., Jagadeesh, Karthik, Zhang, Yan, Duan, Yifan, Ievlev, Vitaly, Wells, Kristen L., Rotti, Pavana G., Shahin, Weam, Winter, Michael, Rosen, Bradley H., Evans, Idil, Cai, Qian, Yu, Miao, Walsh, Susan A., Acevedo, Michael R., Pandya, Darpan N., Akurathi, Vamsidhar, Dick, David W., Wadas, Thaddeus J., Joo, Nam Soo, Wine, Jeffrey J., Birket, Susan, Fernandez, Courtney M., Leung, Hui Min, Tearney, Guillermo J., Verkman, Alan S., Haggie, Peter M., Scott, Kathleen, Bartels, Douglas, Meyerholz, David K., Rowe, Steven M., Liu, Xiaoming, Yan, Ziying, Haber, Adam L., Sun, Xingshen, Engelhardt, John F.

Issue&Volume: 2023-09-20

Abstract: Speciation leads to adaptive changes in organ cellular physiology and creates challenges for studying rare cell-type functions that diverge between humans and mice. Rare cystic fibrosis transmembrane conductance regulator (CFTR)-rich pulmonary ionocytes exist throughout the cartilaginous airways of humans1,2, but limited presence and divergent biology in the proximal trachea of mice has prevented the use of traditional transgenic models to elucidate ionocyte functions in the airway. Here we describe the creation and use of conditional genetic ferret models to dissect pulmonary ionocyte biology and function by enabling ionocyte lineage tracing (FOXI1-CreERT2::ROSA-TG), ionocyte ablation (FOXI1-KO) and ionocyte-specific deletion of CFTR (FOXI1-CreERT2::CFTRL/L). By comparing these models with cystic fibrosis ferrets3,4, we demonstrate that ionocytes control airway surface liquid absorption, secretion, pH and mucus viscosity—leading to reduced airway surface liquid volume and impaired mucociliary clearance in cystic fibrosis, FOXI1-KO and FOXI1-CreERT2::CFTRL/L ferrets. These processes are regulated by CFTR-dependent ionocyte transport of Cl and HCO3. Single-cell transcriptomics and in vivo lineage tracing revealed three subtypes of pulmonary ionocytes and a FOXI1-lineage common rare cell progenitor for ionocytes, tuft cells and neuroendocrine cells during airway development. Thus, rare pulmonary ionocytes perform critical CFTR-dependent functions in the proximal airway that are hallmark features of cystic fibrosis airway disease. These studies provide a road map for using conditional genetics in the first non-rodent mammal to address gene function, cell biology and disease processes that have greater evolutionary conservation between humans and ferrets.

DOI: 10.1038/s41586-023-06549-9

Source: https://www.nature.com/articles/s41586-023-06549-9

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