Zuo Wu-Lin, Yang Jing, Gomi Kazunori, Chao IonWa, Crystal Ronald G, Shaykhiev Renat
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA.
Stem Cells. 2017 Mar;35(3):824-837. doi: 10.1002/stem.2512. Epub 2016 Nov 17.
The airway epithelium of cigarette smokers undergoes dramatic remodeling with hyperplasia of basal cells (BC) and mucus-producing cells, squamous metaplasia, altered ciliated cell differentiation and decreased junctional barrier integrity, relevant to chronic obstructive pulmonary disease and lung cancer. In this study, we show that epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) is induced by smoking in human airway epithelium as a result of epidermal growth factor (EGF)-driven squamous differentiation of airway BC stem/progenitor cells. In turn, AREG induced a unique EGFR activation pattern in human airway BC, distinct from that evoked by EGF, leading to BC- and mucous hyperplasia, altered ciliated cell differentiation and impaired barrier integrity. Further, AREG promoted its own expression and suppressed expression of EGF, establishing an autonomous self-amplifying signaling loop in airway BC relevant for promotion of EGF-independent hyperplastic phenotypes. Thus, EGF-AREG interplay in airway BC stem/progenitor cells is one of the mechanisms that mediates the interconnected pathogenesis of all major smoking-induced lesions in the human airway epithelium. Stem Cells 2017;35:824-837.
吸烟者的气道上皮会发生显著重塑，包括基底细胞（BC）和黏液分泌细胞增生、鳞状化生、纤毛细胞分化改变以及连接屏障完整性降低，这些都与慢性阻塞性肺疾病和肺癌相关。在本研究中，我们发现表皮生长因子受体（EGFR）配体双调蛋白（AREG）在人气道上皮中由吸烟诱导产生，这是由于表皮生长因子（EGF）驱动气道BC干/祖细胞发生鳞状分化所致。反过来，AREG在人气道BC中诱导了一种独特的EGFR激活模式，不同于EGF所引发的模式，导致BC和黏液增生、纤毛细胞分化改变以及屏障完整性受损。此外，AREG促进自身表达并抑制EGF表达，在气道BC中建立了一个自主的自我放大信号环，这与促进不依赖EGF的增生表型相关。因此，气道BC干/祖细胞中的EGF - AREG相互作用是介导人类气道上皮中所有主要吸烟诱导病变相互关联发病机制的机制之一。《干细胞》2017年；35卷：824 - 837页
