The angiotensin-converting enzyme 2 (ACE2) is a primary cell surface viral binding receptor for SARS-CoV-2, so finding new regulatory molecules to modulate ACE2 expression levels is a promising strategy against COVID-19. In the current study, we utilized islet organoids derived from human embryonic stem cells (hESCs), animal models and COVID-19 patients to discover that fibroblast growth factor 7 (FGF7) enhances ACE2 expression within the islets, facilitating SARS-CoV-2 infection and resulting in impaired insulin secretion. Using hESC-derived islet organoids, we demonstrated that FGF7 interacts with FGF receptor 2 (FGFR2) and FGFR1 to upregulate ACE2 expression predominantly in β cells. This upregulation increases both insulin secretion and susceptibility of β cells to SARS-CoV-2 infection. Inhibiting FGFR counteracts the FGF7-induced ACE2 upregulation, subsequently reducing viral infection and replication in the islets. Furthermore, retrospective clinical data revealed that diabetic patients with severe COVID-19 symptoms exhibited elevated serum FGF7 levels compared to those with mild symptoms. Finally, animal experiments indicated that SARS-CoV-2 infection increased pancreatic FGF7 levels, resulting in a reduction of insulin concentrations in situ. Taken together, our research offers a potential regulatory strategy for ACE2 by controlling FGF7, thereby protecting islets from SARS-CoV-2 infection and preventing the progression of diabetes in the context of COVID-19.

血管紧张素转换酶 2 (ACE2) 是 SARS-CoV-2 的主要细胞表面病毒结合受体，因此寻找新的调节分子来调节 ACE2 表达水平是对抗 COVID-19 的一种有前景的策略。在当前的研究中，我们利用源自人类胚胎干细胞 (hESC)、动物模型和 COVID-19 患者的胰岛类器官，发现成纤维细胞生长因子 7 (FGF7) 增强胰岛内的 ACE2 表达，促进 SARS-CoV-2 感染并导致胰岛素分泌受损。使用 hESC 衍生的胰岛类器官，我们证明 FGF7 与 FGF 受体 2 (FGFR2) 和 FGFR1 相互作用，主要上调 β 细胞中 ACE2 的表达。这种上调会增加胰岛素分泌和 β 细胞对 SARS-CoV-2 感染的敏感性。抑制 FGFR 可以抵消 FGF7 诱导的 ACE2 上调，从而减少胰岛中的病毒感染和复制。此外，回顾性临床数据显示，与症状较轻的糖尿病患者相比，患有严重 COVID-19 症状的糖尿病患者的血清 FGF7 水平升高。最后，动物实验表明，SARS-CoV-2 感染增加了胰腺 FGF7 水平，导致原位胰岛素浓度降低。总而言之，我们的研究通过控制 FGF7 为 ACE2 提供了一种潜在的调控策略，从而保护胰岛免受 SARS-CoV-2 感染，并预防 COVID-19 背景下糖尿病的进展。