SOX21 modulates SOX2-initiated differentiation of epithelial cells in the extrapulmonary airways.
SOX21 modulates SOX2-initiated differentiation of epithelial cells in the extrapulmonary airways.
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DOI：
10.7554/elife.57325
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发表时间：
2021-07-21
期刊：
影响因子：
7.7
通讯作者：
Rottier RJ
中科院分区：
文献类型：
--
作者：
Eenjes E;Buscop-van Kempen M;Boerema-de Munck A;Edel GG;Benthem F;de Kreij-de Bruin L;Schnater M;Tibboel D;Collins J;Rottier RJ
在发育和再生过程中，SOX2的表达水平对于维持和分化气道祖细胞之间的平衡至关重要。在这里，我们描述了SOX21对小鼠近端呼吸道上皮的模式，这与发育过程中SOX2的高水平不谋而合。SOX2+/SOX21+区的气道祖细胞向基底层细胞分化，为肺外呼吸道指定细胞。SOX21的缺失表明，在小鼠肺发育过程中，SOX2+祖细胞向基细胞和纤毛细胞的分化增加。我们提出了一种机制，SOX21通过拮抗SOX2诱导的与气道分化相关的特定基因的表达来抑制气道祖细胞的分化。此外，在成人气管上皮中，SOX21抑制基底层到纤毛细胞的分化。SOX21的这种分化抑制作用与SOX2相反，SOX2在损伤后的发育和再生过程中主要驱动上皮细胞的分化。此外，利用人胎肺器官和成人支气管上皮细胞，我们证明了SOX2+/SOX21+区域化是保守的。最后，我们发现SOX2和SOX21之间的相互作用是上下文和浓度依赖的，导致了对呼吸道上皮细胞分化的调节。
SOX2 expression levels are crucial for the balance between maintenance and differentiation of airway progenitor cells during development and regeneration. Here, we describe patterning of the mouse proximal airway epithelium by SOX21, which coincides with high levels of SOX2 during development. Airway progenitor cells in this SOX2+/SOX21+ zone show differentiation to basal cells, specifying cells for the extrapulmonary airways. Loss of SOX21 showed an increased differentiation of SOX2+ progenitor cells to basal and ciliated cells during mouse lung development. We propose a mechanism where SOX21 inhibits differentiation of airway progenitors by antagonizing SOX2-induced expression of specific genes involved in airway differentiation. Additionally, in the adult tracheal epithelium, SOX21 inhibits basal to ciliated cell differentiation. This suppressing function of SOX21 on differentiation contrasts SOX2, which mainly drives differentiation of epithelial cells during development and regeneration after injury. Furthermore, using human fetal lung organoids and adult bronchial epithelial cells, we show that SOX2+/SOX21+ regionalization is conserved. Lastly, we show that the interplay between SOX2 and SOX21 is context and concentration dependent leading to regulation of differentiation of the airway epithelium.