1] Department of Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305-5307, USA [2] Department of Internal Medicine, Division of Pulmonary and Critical Care, Stanford University School of Medicine, Stanford, California 94305-5307, USA.
Department of Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305-5307, USA.
Nature. 2014 Mar 13;507(7491):190-4. doi: 10.1038/nature12930. Epub 2014 Feb 5.
Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from AT2 cells, but recent studies propose other sources. Here we use molecular markers, lineage tracing and clonal analysis to map alveolar progenitors throughout the mouse lifespan. We show that, during development, AT1 and AT2 cells arise directly from a bipotent progenitor, whereas after birth new AT1 cells derive from rare, self-renewing, long-lived, mature AT2 cells that produce slowly expanding clonal foci of alveolar renewal. This stem-cell function is broadly activated by AT1 injury, and AT2 self-renewal is selectively induced by EGFR (epidermal growth factor receptor) ligands in vitro and oncogenic Kras(G12D) in vivo, efficiently generating multifocal, clonal adenomas. Thus, there is a switch after birth, when AT2 cells function as stem cells that contribute to alveolar renewal, repair and cancer. We propose that local signals regulate AT2 stem-cell activity: a signal transduced by EGFR-KRAS controls self-renewal and is hijacked during oncogenesis, whereas another signal controls reprogramming to AT1 fate.
肺泡是由扁平状的肺泡Ⅰ型(AT1)细胞和立方形、分泌表面活性剂的肺泡Ⅱ型(AT2)细胞排列而成的气体交换囊。经典研究表明 AT1 细胞由 AT2 细胞分化而来,但最近的研究提出了其他来源。在这里,我们使用分子标记物、谱系追踪和克隆分析来描绘整个小鼠生命周期中的肺泡祖细胞。我们表明,在发育过程中,AT1 和 AT2 细胞直接由一个双能祖细胞产生,而在出生后,新的 AT1 细胞来源于罕见的、自我更新的、长寿的、成熟的 AT2 细胞,这些细胞产生缓慢扩张的肺泡更新克隆焦点。这种干细胞功能在 AT1 损伤后广泛激活,而 AT2 自我更新在体外被 EGFR(表皮生长因子受体)配体和体内致癌 Kras(G12D)选择性诱导,有效地产生多灶性、克隆性腺瘤。因此,在出生后会发生一个转变,此时 AT2 细胞作为干细胞,有助于肺泡更新、修复和癌症。我们提出,局部信号调节 AT2 干细胞活性:由 EGFR-KRAS 转导的信号控制自我更新,并在癌变过程中被劫持,而另一个信号控制向 AT1 命运的重编程。