Jin Li-Li, Yin Yi-Ling, Li Fei-Wei, Zhou Yu-Mei, Chen Wen, Tian Ye, Feng Xiao, Xu Yi, Chen Peng-Fei, Zhang Jin-San, Xu Hui-Jing
National Clinical Research Center for Ocular Disease, School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, 270 West Xueyuan Road, Wenzhou, 325027, Zhejiang, China.
International Collaborative Center On Growth Factor Research, and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
J Mol Histol. 2024 Dec 18;56(1):45. doi: 10.1007/s10735-024-10328-9.
Pancreatic development is a complex process vital for maintaining metabolic balance, requiring intricate interactions among different cell types and signaling pathways. Fibroblast growth factor receptors 2b (FGFR2b)-ligands signaling from adjacent mesenchymal cells is crucial in initiating pancreatic development and differentiating exocrine and endocrine cells through a paracrine mechanism. However, the precise critical time window that affects pancreatic development remains unclear. To explore the roles of FGFR2b-ligands and identify the narrow window of time during which FGFR2b-ligand signaling affects pancreatic development, we used an inducible mouse model to control the expression of soluble dominant-negative FGFR2b (sFGFR2b) at various stages of pancreatic development. Our findings revealed a significant effect of FGFR2b-ligand signaling on epithelial morphology, lumen formation, and pancreatic branching during primary and secondary transition stages. Additionally, sFGFR2b expression reduced the number of Pdx1+ progenitor cells and altered the pancreatic islet structure. Furthermore, we examined the effect of mutation in FGF10, an FGFR2b ligand, on embryonic pancreatic β-cell function. FGF10 null mutant embryos exhibited reduced pancreatic size and a decrease number of islet-like structure. Although neonatal mice with haploinsufficiency for FGF10 exhibited abnormal glucose tolerance test results, indicating a potential diabetes predisposition, these abnormalities normalized with age, aligning with observations in wild type mice. Our study underscores the critical role of FGFR2b-ligand signaling in pancreatic development and postnatal islet function, offering insights into potential therapeutic targets for pancreatic disorders.
胰腺发育是一个对维持代谢平衡至关重要的复杂过程，需要不同细胞类型和信号通路之间进行复杂的相互作用。来自相邻间充质细胞的成纤维细胞生长因子受体2b（FGFR2b）-配体信号传导对于启动胰腺发育以及通过旁分泌机制分化外分泌和内分泌细胞至关重要。然而，影响胰腺发育的确切关键时间窗口仍不清楚。为了探索FGFR2b-配体的作用并确定FGFR2b-配体信号传导影响胰腺发育的狭窄时间窗口，我们使用了一种可诱导的小鼠模型来控制可溶性显性负性FGFR2b（sFGFR2b）在胰腺发育各个阶段的表达。我们的研究结果揭示了FGFR2b-配体信号传导在初级和次级过渡阶段对上皮形态、管腔形成和胰腺分支有显著影响。此外，sFGFR2b的表达减少了Pdx1+祖细胞的数量并改变了胰岛结构。此外，我们研究了FGFR2b配体FGF10的突变对胚胎胰腺β细胞功能的影响。FGF10基因敲除突变胚胎的胰腺尺寸减小，胰岛样结构数量减少。虽然FGF10单倍剂量不足的新生小鼠葡萄糖耐量试验结果异常，表明有潜在的糖尿病易感性，但这些异常随着年龄增长而恢复正常，这与野生型小鼠的观察结果一致。我们的研究强调了FGFR2b-配体信号传导在胰腺发育和出生后胰岛功能中的关键作用，为胰腺疾病的潜在治疗靶点提供了见解。
