Pan Jie-Hong, Adair-Kirk Tracy L, Patel Anand C, Huang Tao, Yozamp Nicholas S, Xu Jian, Reddy E Premkumar, Byers Derek E, Pierce Richard A, Holtzman Michael J, Brody Steven L
Department of Medicine, Washington University, St. Louis, Missouri, USA.
Stem Cells. 2014 Dec;32(12):3245-56. doi: 10.1002/stem.1814.
The epithelium of the pulmonary airway is specially differentiated to provide defense against environmental insults, but also subject to dysregulated differentiation that results in lung disease. The current paradigm for airway epithelial differentiation is a one-step program whereby a p63(+) basal epithelial progenitor cell generates a ciliated or secretory cell lineage, but the cue for this transition and whether there are intermediate steps are poorly defined. Here, we identify transcription factor Myb as a key regulator that permits early multilineage differentiation of airway epithelial cells. Myb(+) cells were identified as p63(-) and therefore distinct from basal progenitor cells, but were still negative for markers of differentiation. Myb RNAi treatment of primary-culture airway epithelial cells and Myb gene deletion in mice resulted in a p63(-) population with failed maturation of Foxj1(+) ciliated cells as well as Scbg1a1(+) and Muc5ac(+) secretory cells. Consistent with these findings, analysis of whole genome expression of Myb-deficient cells identified Myb-dependent programs for ciliated and secretory cell differentiation. Myb(+) cells were rare in human airways but were increased in regions of ciliated cells and mucous cell hyperplasia in samples from subjects with chronic obstructive pulmonary disease. Together, the results show that a p63(-) Myb(+) population of airway epithelial cells represents a distinct intermediate stage of differentiation that is required under normal conditions and may be heightened in airway disease.
肺气道上皮经过特殊分化，既能抵御环境侵害，也易因分化失调而引发肺部疾病。目前关于气道上皮分化的模式是一个单步程序，即p63(+)基底上皮祖细胞产生纤毛或分泌细胞谱系，但这种转变的线索以及是否存在中间步骤尚不清楚。在此，我们确定转录因子Myb是气道上皮细胞早期多谱系分化的关键调节因子。Myb(+)细胞被鉴定为p63(-)，因此与基底祖细胞不同，但仍为分化标志物阴性。对原代培养的气道上皮细胞进行Myb RNA干扰处理以及在小鼠中删除Myb基因，导致出现一个p63(-)群体，其中Foxj1(+)纤毛细胞以及Scbg1a1(+)和Muc5ac(+)分泌细胞成熟失败。与这些发现一致，对Myb缺陷细胞的全基因组表达分析确定了Myb依赖性的纤毛和分泌细胞分化程序。Myb(+)细胞在人类气道中很少见，但在慢性阻塞性肺疾病患者样本中，在纤毛细胞和黏液细胞增生区域有所增加。总之，结果表明气道上皮细胞的p63(-) Myb(+)群体代表了一个独特的分化中间阶段，在正常情况下是必需的，在气道疾病中可能会加剧。
