Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences; Peking University International Cancer Institute; MOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, 100191, Beijing, China.
Department of Histology and Embryology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China.
Cell Death Dis. 2023 Oct 13;14(10):675. doi: 10.1038/s41419-023-06184-2.
Myoepithelium plays an important role in mammary gland development, but less is known about the molecular mechanism underlying how myoepithelium controls acinus differentiation during gestation. Herein, we found that loss of Kindlin-2 in myoepithelial cells impaired mammary morphogenesis, alveologenesis, and lactation. Using five genetically modified mouse lines combined with single-cell RNA sequencing, we found a Kindlin-2-Stat3-Dll1 signaling cascade in myoepithelial cells that inactivates Notch signaling in luminal cells and consequently drives luminal progenitor commitment to alveolar cells identity. Single-cell profiling revealed that Kindlin-2 loss significantly reduces the proportion of matured alveolar cells. Mechanistically, Kindlin-2 depletion in myoepithelial cells promotes Stat3 activation and upregulates Dll1, which activates the Notch pathway in luminal cells and inhibits luminal progenitor differentiation and maturation during gestation. Inhibition of Notch1 with tangeretin allowed luminal progenitors to regain commitment ability in the pregnant mice with Kindlin-2 depletion in myoepithelium. Taken together, we demonstrated that Kindlin-2 is essential to myoepithelium-controlled luminal progenitors to alveoli transition during gestation.
肌上皮在乳腺发育中起着重要作用，但对于肌上皮如何控制妊娠期间腺泡分化的分子机制知之甚少。本文发现，肌上皮细胞中 Kindlin-2 的缺失会损害乳腺形态发生、肺泡形成和泌乳。使用五种基因修饰小鼠品系结合单细胞 RNA 测序，我们在肌上皮细胞中发现了一个 Kindlin-2-Stat3-Dll1 信号级联，该级联使腔细胞中的 Notch 信号失活，并促使腔前体细胞向肺泡细胞身份的特化。单细胞分析显示，Kindlin-2 的缺失显著降低了成熟肺泡细胞的比例。在机制上，肌上皮细胞中 Kindlin-2 的耗竭促进了 Stat3 的激活和 Dll1 的上调，后者激活了腔细胞中的 Notch 通路，并抑制了妊娠期间腔前体细胞的分化和成熟。用 tangeretin 抑制 Notch1 可使在肌上皮细胞中耗尽 Kindlin-2 的妊娠小鼠中的腔前体细胞恢复特化能力。总之，我们证明了 Kindlin-2 对于肌上皮细胞控制妊娠期间的腔前体细胞向肺泡的过渡是必不可少的。
