FXYD2 marks and regulates maturity of β cells via ion channel-mediated signal transduction
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...
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Nature Portfolio
2025-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60188-4 |
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| author | Clarissa Tacto Meghan Tahbaz Andrew Salib Shudi Wang Fritz Cayabyab Jinhyuk Choi Kiyoka Kim Yu Hamba Harvey Perez Paul D. Gershon Robert Damoiseaux Tae Gyu Oh Eiji Yoshihara |
| author_facet | Clarissa Tacto Meghan Tahbaz Andrew Salib Shudi Wang Fritz Cayabyab Jinhyuk Choi Kiyoka Kim Yu Hamba Harvey Perez Paul D. Gershon Robert Damoiseaux Tae Gyu Oh Eiji Yoshihara |
| author_sort | Clarissa Tacto |
| collection | DOAJ |
| description | 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 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 FXYD2High HILOs significantly outperform FXYD2Low 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. |
| format | Article |
| id | doaj-art-b4cc6848675d43dfaf28aa16b62d0db9 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b4cc6848675d43dfaf28aa16b62d0db92025-08-20T02:05:41ZengNature PortfolioNature Communications2041-17232025-06-0116112010.1038/s41467-025-60188-4FXYD2 marks and regulates maturity of β cells via ion channel-mediated signal transductionClarissa Tacto0Meghan Tahbaz1Andrew Salib2Shudi Wang3Fritz Cayabyab4Jinhyuk Choi5Kiyoka Kim6Yu Hamba7Harvey Perez8Paul D. Gershon9Robert Damoiseaux10Tae Gyu Oh11Eiji Yoshihara12The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterDepartment of Molecular Biology and Biochemistry, University of California IrvineDepartment of Bioengineering in the Samueli School of Engineering, University of California Los AngelesDepartment of Oncology Science, University of Oklahoma Health Sciences CenterThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterAbstract 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 FXYD2High HILOs significantly outperform FXYD2Low 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.https://doi.org/10.1038/s41467-025-60188-4 |
| spellingShingle | Clarissa Tacto Meghan Tahbaz Andrew Salib Shudi Wang Fritz Cayabyab Jinhyuk Choi Kiyoka Kim Yu Hamba Harvey Perez Paul D. Gershon Robert Damoiseaux Tae Gyu Oh Eiji Yoshihara FXYD2 marks and regulates maturity of β cells via ion channel-mediated signal transduction Nature Communications |
| title | FXYD2 marks and regulates maturity of β cells via ion channel-mediated signal transduction |
| title_full | FXYD2 marks and regulates maturity of β cells via ion channel-mediated signal transduction |
| title_fullStr | FXYD2 marks and regulates maturity of β cells via ion channel-mediated signal transduction |
| title_full_unstemmed | FXYD2 marks and regulates maturity of β cells via ion channel-mediated signal transduction |
| title_short | FXYD2 marks and regulates maturity of β cells via ion channel-mediated signal transduction |
| title_sort | fxyd2 marks and regulates maturity of β cells via ion channel mediated signal transduction |
| url | https://doi.org/10.1038/s41467-025-60188-4 |
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