Centeio Raquel, Cabrita Inês, Schreiber Rainer, Kunzelmann Karl
Physiological Institute, University of Regensburg, Regensburg, Germany.
Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Front Physiol. 2023 May 9;14:1157704. doi: 10.3389/fphys.2023.1157704. eCollection 2023.
Cl channels such as the Ca activated Cl channel TMEM16A and the Cl permeable phospholipid scramblase TMEM16F may affect the intracellular Cl concentration ([Cl]), which could act as an intracellular signal. Loss of airway expression of TMEM16A induced a massive expansion of the secretory cell population like goblet and club cells, causing differentiation into a secretory airway epithelium. Knockout of the Ca-activated Cl channel TMEM16A or the phospholipid scramblase TMEM16F leads to mucus accumulation in intestinal goblet cells and airway secretory cells. We show that both TMEM16A and TMEM16F support exocytosis and release of exocytic vesicles, respectively. Lack of TMEM16A/F expression therefore causes inhibition of mucus secretion and leads to goblet cell metaplasia. The human basal epithelial cell line BCi-NS1.1 forms a highly differentiated mucociliated airway epithelium when grown in PneumaCult™ media under an air liquid interface. The present data suggest that mucociliary differentiation requires activation of Notch signaling, but not the function of TMEM16A. Taken together, TMEM16A/F are important for exocytosis, mucus secretion and formation of extracellular vesicles (exosomes or ectosomes) but the present data do no not support a functional role of TMEM16A/F in Notch-mediated differentiation of BCi-NS1.1 cells towards a secretory epithelium.
氯离子通道，如钙激活氯离子通道TMEM16A和氯离子通透磷脂翻转酶TMEM16F，可能会影响细胞内氯离子浓度（[Cl]），而这可能作为一种细胞内信号。气道中TMEM16A表达缺失会导致分泌细胞群体大量扩张，如杯状细胞和棒状细胞，从而分化为分泌型气道上皮。敲除钙激活氯离子通道TMEM16A或磷脂翻转酶TMEM16F会导致肠道杯状细胞和气道分泌细胞中黏液积聚。我们发现TMEM16A和TMEM16F分别支持胞吐作用和胞吐小泡的释放。因此，缺乏TMEM16A/F表达会导致黏液分泌受到抑制，并导致杯状细胞化生。人基底上皮细胞系BCi-NS1.1在气液界面下的PneumaCult™培养基中生长时，会形成高度分化的黏液纤毛气道上皮。目前的数据表明，黏液纤毛分化需要Notch信号通路的激活，但不需要TMEM16A的功能。综上所述，TMEM16A/F对于胞吐作用、黏液分泌和细胞外囊泡（外泌体或微囊泡）的形成很重要，但目前的数据不支持TMEM16A/F在Notch介导的BCi-NS1.1细胞向分泌型上皮细胞分化中发挥功能作用。
