Jiang Simin, Chen Dian, Tian Liangliang, Pan Zihang, Long Huanyu, Chu Lanhe, Kong Weijing, Yao Qiyang, Ma Xiaojing, Zhao Yun, Wang Kai, Chen Yahong
Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China.
Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Clinical Stem Cell Research Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing 100191, China.
Biomedicines. 2025 Jul 2;13(7):1623. doi: 10.3390/biomedicines13071623.
: The bone morphogenetic protein (BMP) signaling pathway is essential for lung development. BMP4, a key regulator, binds to type I (BMPR1) and type II (BMPR2) receptors to initiate downstream signaling. While the inactivation of and leads to tracheoesophageal fistulae, the role of mutations in lung epithelial development remains unclear. : We generated induced pluripotent stem cells (iPSCs) from a patient carrying a BMPR2 mutation (c.631C>T), and gene-corrected isogenic controls were created using CRISPR/Cas9. These iPSCs were differentiated into lung progenitor cells and subsequently cultured to generate alveolar and airway organoids. The differentiation efficiency and epithelial lineage specification were assessed using immunofluorescence, flow cytometry, and qRT-PCR. : BMPR2-mutant iPSCs showed no impairment in forming a definitive or anterior foregut endoderm. However, a significant reduction in lung progenitor cell differentiation was observed. Further, while alveolar epithelial differentiation remained largely unaffected, airway organoids derived from BMPR2-mutant cells exhibited impaired goblet and ciliated cell development, with an increase in basal and club cell markers, indicating skewing toward undifferentiated airway cell populations. : BMPR2 dysfunction selectively impairs late-stage lung progenitor specification and disrupts airway epithelial maturation, providing new insights into the developmental impacts of BMPR2 mutations.
骨形态发生蛋白（BMP）信号通路对肺发育至关重要。关键调节因子BMP4与I型（BMPR1）和II型（BMPR2）受体结合以启动下游信号传导。虽然 和 的失活会导致气管食管瘘，但BMPR2突变在肺上皮发育中的作用仍不清楚。：我们从一名携带BMPR2突变（c.631C>T）的患者中生成了诱导多能干细胞（iPSC），并使用CRISPR/Cas9创建了基因校正的同基因对照。这些iPSC分化为肺祖细胞，随后进行培养以生成肺泡和气道类器官。使用免疫荧光、流式细胞术和qRT-PCR评估分化效率和上皮谱系特异性。：BMPR2突变的iPSC在形成明确的或前肠内胚层方面没有受损。然而，观察到肺祖细胞分化显著减少。此外，虽然肺泡上皮分化在很大程度上未受影响，但源自BMPR2突变细胞的气道类器官显示杯状细胞和纤毛细胞发育受损，基底细胞和棒状细胞标志物增加，表明向未分化的气道细胞群体倾斜。：BMPR2功能障碍选择性地损害晚期肺祖细胞特化并破坏气道上皮成熟，为BMPR2突变的发育影响提供了新的见解。
