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.

异常的上皮重编程可在组织损伤部位诱导化生分化，最终形成由疤痕和化生上皮组成的转化屏障。虽然上皮干细胞的可塑性已得到很好的表征，但生态位的身份和作用尚未在化生中描述。在这里，我们发现Gli1 ⁺间充质基质细胞 (MSC)，之前显示在疤痕形成过程中促进肌成纤维细胞，促进气道祖细胞化生分化为 KRT5 ⁺基底细胞。在纤维化修复过程中，Gli1 ⁺MSC 整合 hedgehog 激活信号以上调促进化生的祖细胞生态位中的 BMP 拮抗作用。恢复 BMP 激活的平衡减弱了化生 KRT5 ⁺分化，同时促进适应性肺泡分化为 SFTPC ⁺上皮细胞。最后，纤维化的人肺在化生上皮中表现出改变的 BMP 活化。这些发现表明，Gli1 ⁺ MSC 将 hedgehog 信号整合为变阻器，以控制祖细胞生态位中的 BMP 激活，从而确定纤维化的再生结果。