FXYD2 marks and regulates maturity of beta cells via ion channel-mediated signal transduction.
Publication Year:
2025
PubMed ID:
40467586
Funding Grants:
Public Summary:
Diabetes is a condition where the body struggles to regulate blood sugar levels, often due to problems with insulin-producing cells in the pancreas. Scientists are working on ways to replace these damaged cells, and one promising approach involves growing new ones in the lab using human stem cells. These lab-grown clusters, called human islet-like organoids (HILOs), are designed to mimic the function of natural pancreatic islets.
However, a major challenge has been that these lab-grown cells often don’t work as well as the real thing. They may not respond properly to sugar in the blood or may produce insulin inconsistently. This study sheds light on why that happens—and how we might fix it.
This study describes a key role for a protein called FXYD2 in helping these lab-grown cells mature and function more like natural insulin-producing cells. In healthy human pancreatic cells, FXYD2 is present at high levels. But in the lab-grown versions, it’s often missing or reduced. The team found that when HILOs had higher levels of FXYD2, they were much better at sensing sugar and releasing insulin in response—just like real pancreatic cells.
The study shows that FXYD2 interacts with another protein called SRC, which helps send signals inside the cell. Together, they influence a pathway that controls which genes are turned on or off in the insulin-producing cells. This signaling pathway helps the cells develop the right features to do their job effectively. To test whether this discovery could make a real difference, the researchers transplanted HILOs with high levels of FXYD2 into diabetic mice. The results were striking: these mice had better blood sugar control compared to those that received cells with low FXYD2 levels.
This breakthrough suggests that FXYD2 could be used as a marker to identify the most functional lab-grown insulin-producing cells. It could also be a target for improving how these cells are made in the lab, bringing us closer to reliable, stem cell-based therapies for diabetes. In short, this study offers new hope for creating better, more effective treatments for people with diabetes—by helping lab-grown cells act more like the real thing.
Scientific Abstract:
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 beta cell transcriptome necessary for glucose-stimulated insulin secretion (GSIS). Despite its presence in mature beta cells, FXYD2 is diminished in hPSC-derived beta-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 beta cell transcriptome. We demonstrate that FXYD2(High) HILOs significantly outperform FXYD2(Low) counterparts to improve hyperglycemia in STZ-induced diabetic immune deficient mice. These results suggest that FXYD2 marks and regulates human beta 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.
