Department of Medicine, Division of Pulmonary and Critical Care Medicine, Cardiovascular Research Institute, San Francisco, CA, USA.
Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
Nat Cell Biol. 2020 Nov;22(11):1295-1306. doi: 10.1038/s41556-020-00591-9. Epub 2020 Oct 12.
Aberrant epithelial reprogramming can induce metaplastic differentiation at sites of tissue injury that culminates in transformed barriers composed of scar and metaplastic epithelium. While the plasticity of epithelial stem cells is well characterized, the identity and role of the niche has not been delineated in metaplasia. Here, we show that Gli1 mesenchymal stromal cells (MSCs), previously shown to contribute to myofibroblasts during scarring, promote metaplastic differentiation of airway progenitors into KRT5 basal cells. During fibrotic repair, Gli1 MSCs integrate hedgehog activation signalling to upregulate BMP antagonism in the progenitor niche that promotes metaplasia. Restoring the balance towards BMP activation attenuated metaplastic KRT5 differentiation while promoting adaptive alveolar differentiation into SFTPC epithelium. Finally, fibrotic human lungs demonstrate altered BMP activation in the metaplastic epithelium. These findings show that Gli1 MSCs integrate hedgehog signalling as a rheostat to control BMP activation in the progenitor niche to determine regenerative outcome in fibrosis.
上皮细胞异常重编程可诱导组织损伤部位的化生分化，最终形成由瘢痕和化生上皮组成的转化屏障。尽管上皮干细胞的可塑性已得到很好的描述，但在化生过程中，龛的特性和作用尚未明确。在这里，我们表明，先前被证明在瘢痕形成过程中有助于成肌纤维细胞的Gli1 间充质基质细胞 (MSC) 可促进气道祖细胞向 KRT5 基底细胞的化生分化。在纤维化修复过程中，Gli1 MSC 将 Hedgehog 激活信号整合到祖细胞龛中，上调 BMP 拮抗作用，促进化生。恢复向 BMP 激活的平衡可减弱化生的 KRT5 分化，同时促进适应性肺泡分化为 SFTPC 上皮。最后，纤维化的人肺中在化生上皮中表现出改变的 BMP 激活。这些发现表明，Gli1 MSC 将 Hedgehog 信号整合为变阻器，以控制祖细胞龛中的 BMP 激活，从而决定纤维化中的再生结果。
