SPOCK2 controls the proliferation and function of immature pancreatic β-cells through MMP2
Abstract Human pluripotent stem cell-derived β-cells (SC-β-cells) represent an alternative cell source for transplantation in diabetic patients. Although mitogens could in theory be used to expand β-cells, adult β-cells very rarely replicate. In contrast, newly formed β-cells, including SC-β-cells,...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-024-01380-2 |
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| author | Katarzyna Blaszczyk Anna P. Jedrzejak Natalia Ziojla Ekaterina Shcheglova Karolina Szarafin Artur Jankowski Christine A. Beamish Jolanta Chmielowiec Omaima M. Sabek Ashok Balasubramanyam Sanjeet Patel Malgorzata Borowiak |
| author_facet | Katarzyna Blaszczyk Anna P. Jedrzejak Natalia Ziojla Ekaterina Shcheglova Karolina Szarafin Artur Jankowski Christine A. Beamish Jolanta Chmielowiec Omaima M. Sabek Ashok Balasubramanyam Sanjeet Patel Malgorzata Borowiak |
| author_sort | Katarzyna Blaszczyk |
| collection | DOAJ |
| description | Abstract Human pluripotent stem cell-derived β-cells (SC-β-cells) represent an alternative cell source for transplantation in diabetic patients. Although mitogens could in theory be used to expand β-cells, adult β-cells very rarely replicate. In contrast, newly formed β-cells, including SC-β-cells, display higher proliferative capacity and distinct transcriptional and functional profiles. Through bidirectional expression modulation and single-cell RNA-seq, we identified SPOCK2, an ECM protein, as an inhibitor of immature β-cell proliferation. Human β-cells lacking SPOCK2 presented elevated MMP2 expression and activity, leading to β-integrin-FAK-c-JUN pathway activation. Treatment with the MMP2 protein resulted in pronounced short- and long-term SC-β-cell expansion, significantly increasing glucose-stimulated insulin secretion in vitro and in vivo. These findings suggest that SPOCK2 mediates fetal β-cell proliferation and maturation. In summary, we identified a molecular mechanism that specifically regulates SC-β-cell proliferation and function, highlighting a unique signaling milieu of SC-β-cells with promise for the robust derivation of fully functional cells for transplantation. |
| format | Article |
| id | doaj-art-74935d5557d04fedaec5f11a35f649d2 |
| institution | Kabale University |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-74935d5557d04fedaec5f11a35f649d22025-02-09T12:14:13ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-01-0157113115010.1038/s12276-024-01380-2SPOCK2 controls the proliferation and function of immature pancreatic β-cells through MMP2Katarzyna Blaszczyk0Anna P. Jedrzejak1Natalia Ziojla2Ekaterina Shcheglova3Karolina Szarafin4Artur Jankowski5Christine A. Beamish6Jolanta Chmielowiec7Omaima M. Sabek8Ashok Balasubramanyam9Sanjeet Patel10Malgorzata Borowiak11Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz UniversityInstitute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz UniversityInstitute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz UniversityInstitute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz UniversityInstitute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz UniversityInstitute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz UniversityDepartment of Surgery, Methodist Research InstituteCollegium Medicum, University of Warmia and MazuryDepartment of Surgery, Methodist Research InstituteDivision of Diabetes, Endocrinology and Metabolism, Baylor College of MedicineKeck School of Medicine, University of Southern CaliforniaInstitute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz UniversityAbstract Human pluripotent stem cell-derived β-cells (SC-β-cells) represent an alternative cell source for transplantation in diabetic patients. Although mitogens could in theory be used to expand β-cells, adult β-cells very rarely replicate. In contrast, newly formed β-cells, including SC-β-cells, display higher proliferative capacity and distinct transcriptional and functional profiles. Through bidirectional expression modulation and single-cell RNA-seq, we identified SPOCK2, an ECM protein, as an inhibitor of immature β-cell proliferation. Human β-cells lacking SPOCK2 presented elevated MMP2 expression and activity, leading to β-integrin-FAK-c-JUN pathway activation. Treatment with the MMP2 protein resulted in pronounced short- and long-term SC-β-cell expansion, significantly increasing glucose-stimulated insulin secretion in vitro and in vivo. These findings suggest that SPOCK2 mediates fetal β-cell proliferation and maturation. In summary, we identified a molecular mechanism that specifically regulates SC-β-cell proliferation and function, highlighting a unique signaling milieu of SC-β-cells with promise for the robust derivation of fully functional cells for transplantation.https://doi.org/10.1038/s12276-024-01380-2 |
| spellingShingle | Katarzyna Blaszczyk Anna P. Jedrzejak Natalia Ziojla Ekaterina Shcheglova Karolina Szarafin Artur Jankowski Christine A. Beamish Jolanta Chmielowiec Omaima M. Sabek Ashok Balasubramanyam Sanjeet Patel Malgorzata Borowiak SPOCK2 controls the proliferation and function of immature pancreatic β-cells through MMP2 Experimental and Molecular Medicine |
| title | SPOCK2 controls the proliferation and function of immature pancreatic β-cells through MMP2 |
| title_full | SPOCK2 controls the proliferation and function of immature pancreatic β-cells through MMP2 |
| title_fullStr | SPOCK2 controls the proliferation and function of immature pancreatic β-cells through MMP2 |
| title_full_unstemmed | SPOCK2 controls the proliferation and function of immature pancreatic β-cells through MMP2 |
| title_short | SPOCK2 controls the proliferation and function of immature pancreatic β-cells through MMP2 |
| title_sort | spock2 controls the proliferation and function of immature pancreatic β cells through mmp2 |
| url | https://doi.org/10.1038/s12276-024-01380-2 |
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