众所周知，成纤维细胞生长因子受体2（FGFR2）信号对于肺部正常发育至关重要。最近的研究表明，在肺膨胀期（sacculation）期间，上皮FGFR2信号调控AT1和AT2细胞的分化。在肺膨胀期（sacculation）期间，存在三种功能亚型的血小板源性生长因子受体α阳性（PDGFRA+）肺成纤维细胞：收缩肌成纤维细胞、产生ECM的基质成纤维细胞和脂肪成纤维细胞。在肺泡化（alveolarization）期间，这三种亚型都是必需的，以建立一个支持肺泡Ⅱ型上皮细胞（AT2）自我更新和肺泡Ⅰ型上皮细胞（AT1）分化的生态位。FGFR2信号在肺切除术后的肺泡复饰作用中指导PDGFRA+成纤维细胞的收缩肌成纤维细胞分化。然而，在肺膨胀期间，FGFR2信号是否调控PDGFRA+成纤维细胞的收缩肌、基质或脂肪成纤维细胞的分化尚不清楚。在本研究中，通过AT2细胞从E16.5到E18.5表达一个分泌的FGFR2b（dnFGFR2）基因来抑制FGFR2信号。在E18.5、PN7和PN21时分别分析了成纤维细胞和上皮细胞的分化。在所有时间点，收缩肌成纤维细胞数量减少，脂肪/基质成纤维细胞数量增加。出生后，AT2细胞增加，AT1细胞减少，但在E18.5时没有观察到这种差异。同样，在由dnFGFR2肺中的PDGFRA+成纤维细胞制作的器官样体中，观察到AT2细胞增多和AT1细胞减少。采用重组的dnFGFR2b/c处理原代采自E16.5时黏附性肺囊泡成纤维细胞的体外实验结果显示收缩肌成纤维细胞收缩减少。使用PI3K/AKT激活剂740 Y-P处理可以挽救dnFGFR2b/2c引起的缺乏收缩肌成纤维细胞分化。此外，在dnFGFR2肺中分离的E18.5成纤维细胞中，使用PI3K/AKT激活剂740 Y-P处理可以挽救收缩肌成纤维细胞分化的缺陷。

It is well known that Fibroblast Growth Factor Receptor 2 (FGFR2) signaling is critical for proper lung development. Recent studies demonstrate that epithelial FGFR2 signaling during the saccular phase of lung development (sacculation) regulates AT1 and AT2 cell differentiation. During sacculation, Platelet-Derived Growth Factor Receptor Alpha-positive (PDGFRA+) lung fibroblasts exist as three functional subtypes: contractile myofibroblasts, ECM-producing matrix fibroblasts, and lipofibroblasts. All three subtypes are required during alveolarization to establish a niche that supports alveolar type-2 epithelial (AT2) self-renewal and alveolar type-1 epithelial (AT1) differentiation. FGFR2 signaling directs myofibroblast differentiation in PDGFRA+ fibroblasts during alveolar reseptation after pneumonectomy. However, it remains unknown if FGFR2 signaling regulates PDGFRA+ myo-, matrix-, or lipofibroblast differentiation during sacculation. In this study, FGFR2 signaling was inhibited by temporal expression of a secreted dominant-negative FGFR2b (dnFGFR2) by AT2 cells from E16.5 to E18.5. Fibroblast and epithelial differentiation were analyzed at E18.5, PN7, and PN21. At all time points, the number of myofibroblasts was reduced and the number lipo/matrix fibroblasts was increased. AT2 cells are increased and AT1 cells are reduced postnatally, but not at E18.5. Similarly, in organoids made with PDGFRA+ fibroblasts from dnFGFR2 lungs, increased AT2 cells and reduced AT1 cells were observed. In vitro treatment of primary wild-type E16.5 adherent saccular lung fibroblasts with recombinant dnFGFR2b/c resulted in reduced myofibroblast contraction. Treatment with PI3K/AKT activator 740 Y-P rescued the lack of myofibroblast differentiation caused by dnFGFR2b/2c. Moreover, treatment with PI3K/AKT activator 740 Y-P rescued myofibroblast differentiation in E18.5 fibroblasts isolated from dnFGFR2 lungs.