Hawkins Finn, Kotton Darrell N
Pulmonary Center and Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, Massachusetts.
Ann Am Thorac Soc. 2015 Mar;12 Suppl 1:S50-3. doi: 10.1513/AnnalsATS.201410-457MG.
The discovery of embryonic and induced pluripotent stem cells (ESCs and iPSCs) has ushered in an exciting new era of regenerative medicine. Human pluripotent stem cells can be "directed" in vitro toward lung epithelium by applying specific stepwise combinations of growth factors that recapitulate the molecular mechanisms of respiratory development in animal models. In a relatively short time, there has been significant progress in deriving lung epithelium from ESCs/iPSCs. These directed differentiation protocols include high concentrations of activin A to induce definitive endoderm followed by dual inhibition of bone morphogenic protein and TGF-β signaling pathways to produce anterior foregut endoderm. Subsequent stimulation of Wnt, bone morphogenic protein, and fibroblast growth factor signaling leads to lung epithelial lineage specification, identified by the expression of Nkx2.1. These cells subsequently express other markers of the developing lung and a variety of lung epithelial subtypes. The major limitation in the field currently is deriving and characterizing mature, functional lung epithelium. The generation of iPSCs is now well established, and researchers have generated iPSCs from patients with acquired and inherited lung diseases. This platform offers unparalleled opportunities to model lung development and disease using human cells.
胚胎干细胞和诱导多能干细胞（ESCs和iPSCs）的发现开创了再生医学令人兴奋的新时代。通过应用特定的逐步生长因子组合，可在体外将人类多能干细胞“定向”为肺上皮细胞，这些组合概括了动物模型中呼吸发育的分子机制。在相对较短的时间内，从ESCs/iPSCs中获得肺上皮细胞已取得显著进展。这些定向分化方案包括高浓度的激活素A以诱导确定的内胚层，随后双重抑制骨形态发生蛋白和TGF-β信号通路以产生前肠内胚层。随后刺激Wnt、骨形态发生蛋白和成纤维细胞生长因子信号通路，导致肺上皮谱系特化，通过Nkx2.1的表达来确定。这些细胞随后表达发育中肺的其他标志物以及多种肺上皮亚型。目前该领域的主要限制在于获得并表征成熟、有功能的肺上皮细胞。iPSCs的生成现已成熟，研究人员已从患有获得性和遗传性肺病的患者中生成了iPSCs。这个平台为利用人类细胞模拟肺发育和疾病提供了无与伦比的机会。
