Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
Am J Respir Cell Mol Biol. 2019 Nov;61(5):607-619. doi: 10.1165/rcmb.2018-0390OC.
Reciprocal epithelial-mesenchymal interactions are pivotal in lung development, homeostasis, injury, and repair. Organoids have been used to investigate such interactions, but with a major focus on epithelial responses to mesenchyme and less attention to epithelial effects on mesenchyme. In the present study, we used nascent organoids composed of human and mouse lung epithelial and mesenchymal cells to demonstrate that healthy lung epithelium dramatically represses transcriptional, contractile, and matrix synthetic functions of lung fibroblasts. Repression of fibroblast activation requires signaling via the bone morphogenetic protein (BMP) pathway. BMP signaling is diminished after epithelial injury and , and exogenous BMP4 restores fibroblast repression in injured organoids. In contrast, inhibition of BMP signaling in healthy organoids is sufficient to derepress fibroblast matrix synthetic function. Our results reveal potent repression of fibroblast activation by healthy lung epithelium and a novel mechanism by which epithelial loss or injury is intrinsically coupled to mesenchymal activation via loss of repressive BMP signaling.
上皮-间充质的相互作用在肺的发育、稳态、损伤和修复中起着关键作用。类器官已被用于研究这种相互作用，但主要集中在上皮对间充质的反应上，而对上皮对间充质的影响关注较少。在本研究中，我们使用由人源和鼠源肺上皮和间充质细胞组成的新生类器官证明，健康的肺上皮可显著抑制肺成纤维细胞的转录、收缩和基质合成功能。对成纤维细胞激活的抑制需要通过骨形态发生蛋白（BMP）途径进行信号传递。上皮损伤后 BMP 信号会减弱，而且，外源性 BMP4 可恢复损伤类器官中成纤维细胞的抑制作用。相比之下，在健康类器官中抑制 BMP 信号足以解除对成纤维细胞基质合成功能的抑制。我们的研究结果揭示了健康的肺上皮对成纤维细胞激活的强烈抑制作用，以及上皮缺失或损伤通过丧失抑制性 BMP 信号与间充质激活内在耦合的新机制。
