Tacto Clarissa, Tahbaz Meghan, Salib Andrew, Wang Shudi, Cayabyab Fritz, Choi Jinhyuk, Kim Kiyoka, Hamba Yu, Perez Harvey, Gershon Paul D, Damoiseaux Robert, Oh Tae Gyu, Yoshihara Eiji
The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
Nat Commun. 2025 Jun 4;16(1):5110. doi: 10.1038/s41467-025-60188-4.
Human pancreatic islets regulate organ development and metabolic homeostasis, with dysfunction leading to diabetes. Human pluripotent stem cells (hPSCs) provide a potential alternative source to cadaveric human pancreatic islets for replacement therapy in diabetes. However, human islet-like organoids (HILOs) generated from hPSCs in vitro often exhibit heterogeneous immature phenotypes such as aberrant gene expression and inadequate insulin secretion in response to glucose. Here we show that FXYD Domain Containing Ion Transport Regulator 2 (FXYD2) marks and regulates functional maturation and heterogeneity of generated HILOs, by controlling the β cell transcriptome necessary for glucose-stimulated insulin secretion (GSIS). Despite its presence in mature β cells, FXYD2 is diminished in hPSC-derived β-like cells. Mechanistically, we find that FXYD2 physically interacts with SRC proto-oncogene, non-receptor tyrosine kinase (SRC) protein to regulate FXYD2-SRC-TEAD1 signaling to modulate β cell transcriptome. We demonstrate that FXYD2 HILOs significantly outperform FXYD2 counterparts to improve hyperglycemia in STZ-induced diabetic immune deficient mice. These results suggest that FXYD2 marks and regulates human β cell maturation via channel-sensing signal transduction and that it can be used as a selection marker for functional heterogeneity of stem cell derived human islet organoids.
人胰岛调节器官发育和代谢稳态，功能障碍会导致糖尿病。人多能干细胞（hPSC）为糖尿病替代疗法提供了一种潜在的替代尸体人胰岛的来源。然而，体外由hPSC生成的人胰岛样类器官（HILO）通常表现出异质性的未成熟表型，如异常基因表达和对葡萄糖反应时胰岛素分泌不足。在这里，我们表明含FXYD结构域的离子转运调节因子2（FXYD2）通过控制葡萄糖刺激的胰岛素分泌（GSIS）所需的β细胞转录组，标记并调节所生成HILO的功能成熟和异质性。尽管FXYD2存在于成熟β细胞中，但在hPSC衍生的β样细胞中其表达减少。从机制上讲，我们发现FXYD2与原癌基因SRC、非受体酪氨酸激酶（SRC）蛋白发生物理相互作用，以调节FXYD2-SRC-TEAD1信号传导来调节β细胞转录组。我们证明，FXYD2 HILO在改善链脲佐菌素诱导的糖尿病免疫缺陷小鼠的高血糖方面明显优于FXYD2缺失的同类物。这些结果表明，FXYD2通过通道感应信号转导标记并调节人β细胞成熟，并且它可以用作干细胞衍生的人胰岛类器官功能异质性的选择标记。
