Human apical-out nasal organoids reveal an essential role of matrix metalloproteinases in airway epithelial differentiation.
Human apical-out nasal organoids reveal an essential role of matrix metalloproteinases in airway epithelial differentiation.
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DOI：
10.1038/s41467-023-44488-1
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发表时间：
2024-01-02
影响因子：
16.6
通讯作者：
Li, Chunwei
中科院分区：
文献类型：
--
作者：
Li, Liyue;Jiao, Linyi;Feng, Danni;Yuan, Yizhang;Yang, Xiaoqian;Li, Jian;Jiang, Dong;Chen, Hexin;Meng, Qingxiang;Chen, Ruchong;Fang, Bixing;Zou, Xuenong;Luo, Zhenhua;Ye, Xiaoyan;Hong, Yue;Liu, Chun;Li, Chunwei
细胞外基质(ECM)的组装/分解是呼吸道上皮细胞发育和重塑的重要调节因子。呼吸道有机体广泛应用于呼吸系统的研究，但利用体外有机体系统研究ECM组织在上皮细胞生长和分化中的作用和机制的研究较少。此外，目前大多数基于Matrigel的呼吸道有机化合物都是基底面的，进入根尖表面是有挑战性的。我们提出了一种使用生物化学定义的混合水凝胶系统的人的尖端出来的呼吸道有机物质。在人鼻上皮祖细胞分化的过程中，凝胶逐渐降解，导致器质性顶面朝外。基质金属蛋白酶(MMP7、MMP9、MMP10和MMP13)在类器官分化过程中的表达和活性增加，抑制MMPs显著抑制正常调节，导致杯状细胞比例增加。此外，炎症黏膜中杯状细胞增生性上皮中MMPs的表达减少。该系统揭示了上皮源性MMPs在决定上皮细胞命运中的重要作用，并为进一步研究ECM在调节健康和疾病中的呼吸道发育提供了一个适用的平台。Matrigel制成的呼吸道有机物质呈底部向外取向。在这里，作者提出了使用生物化学定义的水凝胶系统的尖端出鼻器，揭示了基质金属蛋白酶是正常的上皮发育所必需的。
Extracellular matrix (ECM) assembly/disassembly is a critical regulator for airway epithelial development and remodeling. Airway organoid is widely used in respiratory research, yet there is limited study to indicate the roles and mechanisms of ECM organization in epithelial growth and differentiation by using in vitro organoid system. Moreover, most of current Matrigel-based airway organoids are in basal-out orientation where accessing the apical surface is challenging. We present a human apical-out airway organoid using a biochemically defined hybrid hydrogel system. During human nasal epithelial progenitor cells (hNEPCs) differentiation, the gel gradually degrade, leading to the organoid apical surfaces facing outward. The expression and activity of ECM-degrading enzymes, matrix metalloproteinases (MMP7, MMP9, MMP10 and MMP13) increases during organoid differentiation, where inhibition of MMPs significantly suppresses the normal ciliation, resulting in increased goblet cell proportion. Moreover, a decrease of MMPs is found in goblet cell hyperplastic epithelium in inflammatory mucosa. This system reveals essential roles of epithelial-derived MMPs on epithelial cell fate determination, and provides an applicable platform enabling further study for ECM in regulating airway development in health and diseases. Airway organoids made in Matrigel are in basal-out orientation. Here, authors present apical-out nasal organoids using a biochemically defined hydrogel system, revealing that matrix metalloproteinases are required for normal epithelial development.
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