TMEM219 regulates the transcription factor expression and proliferation of beta cells
Pancreatic beta cells replenishment is considered the next therapeutic option for type 1 diabetes; while stimulating endogenous beta cells proliferation is the “holy grail” for those patients with exhausted beta cell mass. Here we are demonstrating that the pro-apoptotic receptor TMEM219 is expresse...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Endocrinology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2024.1306127/full |
| _version_ | 1797349422943698944 |
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| author | Francesca D’Addio Francesca D’Addio Emma Assi Anna Maestroni Giada Rossi Vera Usuelli Adriana Petrazzuolo Marta Nardini Marta Nardini Cristian Loretelli Moufida Ben Nasr Moufida Ben Nasr Paolo Fiorina Paolo Fiorina Paolo Fiorina |
| author_facet | Francesca D’Addio Francesca D’Addio Emma Assi Anna Maestroni Giada Rossi Vera Usuelli Adriana Petrazzuolo Marta Nardini Marta Nardini Cristian Loretelli Moufida Ben Nasr Moufida Ben Nasr Paolo Fiorina Paolo Fiorina Paolo Fiorina |
| author_sort | Francesca D’Addio |
| collection | DOAJ |
| description | Pancreatic beta cells replenishment is considered the next therapeutic option for type 1 diabetes; while stimulating endogenous beta cells proliferation is the “holy grail” for those patients with exhausted beta cell mass. Here we are demonstrating that the pro-apoptotic receptor TMEM219 is expressed in fetal pancreas, in beta cell precursors and in in vitro embryonic-derived endocrine progenitors. TMEM219 signaling negatively regulates beta cells at early stages and induces Caspase 8-mediated cell death. Pharmacological blockade of TMEM219 further rescued beta cell precursor and proliferation markers, and decreased cell death, both in islets and in in vitro-derived endocrine progenitors, allowing for beta cell preservation. While addressing the upstream controlling TMEM219 expression, we determined the TMEM219 miRNet; indeed, one of those miRNAs, miR-129-2, is highly expressed in human islets, particularly in patients at risk or with established type 1 diabetes. miR-129-2 mimic downregulated TMEM219 expression in islets, in in vitro embryonic-derived endocrine progenitors and in highly proliferating insulinoma-derived cells. Moreover, miR-129-2 inhibitor induced a TMEM219 overexpression in insulinoma-derived cells, which restored cell proliferation and functional markers, thus acting as endogenous regulator of TMEM219 expression. The TMEM219 upstream regulator miR129-2 controls the fate of beta cell precursors and may unleash their regenerative potentials to replenish beta cells in type 1 diabetes. |
| first_indexed | 2024-03-08T12:30:02Z |
| format | Article |
| id | doaj.art-3c19f5f129a14d3dadfdbfbfd1eeb6c7 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-03-08T12:30:02Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-3c19f5f129a14d3dadfdbfbfd1eeb6c72024-01-22T04:33:40ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922024-01-011510.3389/fendo.2024.13061271306127TMEM219 regulates the transcription factor expression and proliferation of beta cellsFrancesca D’Addio0Francesca D’Addio1Emma Assi2Anna Maestroni3Giada Rossi4Vera Usuelli5Adriana Petrazzuolo6Marta Nardini7Marta Nardini8Cristian Loretelli9Moufida Ben Nasr10Moufida Ben Nasr11Paolo Fiorina12Paolo Fiorina13Paolo Fiorina14International Center for Type 1 Diabetes (T1D), Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences (DIBIC), Università di Milano, Milan, ItalyDivision of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, ItalyInternational Center for Type 1 Diabetes (T1D), Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences (DIBIC), Università di Milano, Milan, ItalyInternational Center for Type 1 Diabetes (T1D), Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences (DIBIC), Università di Milano, Milan, ItalyInternational Center for Type 1 Diabetes (T1D), Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences (DIBIC), Università di Milano, Milan, ItalyInternational Center for Type 1 Diabetes (T1D), Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences (DIBIC), Università di Milano, Milan, ItalyInternational Center for Type 1 Diabetes (T1D), Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences (DIBIC), Università di Milano, Milan, ItalyInternational Center for Type 1 Diabetes (T1D), Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences (DIBIC), Università di Milano, Milan, ItalyNephrology Division, Boston Children’s Hospital and Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United StatesInternational Center for Type 1 Diabetes (T1D), Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences (DIBIC), Università di Milano, Milan, ItalyInternational Center for Type 1 Diabetes (T1D), Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences (DIBIC), Università di Milano, Milan, ItalyNephrology Division, Boston Children’s Hospital and Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United StatesInternational Center for Type 1 Diabetes (T1D), Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences (DIBIC), Università di Milano, Milan, ItalyDivision of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, ItalyNephrology Division, Boston Children’s Hospital and Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United StatesPancreatic beta cells replenishment is considered the next therapeutic option for type 1 diabetes; while stimulating endogenous beta cells proliferation is the “holy grail” for those patients with exhausted beta cell mass. Here we are demonstrating that the pro-apoptotic receptor TMEM219 is expressed in fetal pancreas, in beta cell precursors and in in vitro embryonic-derived endocrine progenitors. TMEM219 signaling negatively regulates beta cells at early stages and induces Caspase 8-mediated cell death. Pharmacological blockade of TMEM219 further rescued beta cell precursor and proliferation markers, and decreased cell death, both in islets and in in vitro-derived endocrine progenitors, allowing for beta cell preservation. While addressing the upstream controlling TMEM219 expression, we determined the TMEM219 miRNet; indeed, one of those miRNAs, miR-129-2, is highly expressed in human islets, particularly in patients at risk or with established type 1 diabetes. miR-129-2 mimic downregulated TMEM219 expression in islets, in in vitro embryonic-derived endocrine progenitors and in highly proliferating insulinoma-derived cells. Moreover, miR-129-2 inhibitor induced a TMEM219 overexpression in insulinoma-derived cells, which restored cell proliferation and functional markers, thus acting as endogenous regulator of TMEM219 expression. The TMEM219 upstream regulator miR129-2 controls the fate of beta cell precursors and may unleash their regenerative potentials to replenish beta cells in type 1 diabetes.https://www.frontiersin.org/articles/10.3389/fendo.2024.1306127/fulltype 1 diabetesendocrine progenitorsTMEM219IGFBP3isletsmature and immature beta cells |
| spellingShingle | Francesca D’Addio Francesca D’Addio Emma Assi Anna Maestroni Giada Rossi Vera Usuelli Adriana Petrazzuolo Marta Nardini Marta Nardini Cristian Loretelli Moufida Ben Nasr Moufida Ben Nasr Paolo Fiorina Paolo Fiorina Paolo Fiorina TMEM219 regulates the transcription factor expression and proliferation of beta cells Frontiers in Endocrinology type 1 diabetes endocrine progenitors TMEM219 IGFBP3 islets mature and immature beta cells |
| title | TMEM219 regulates the transcription factor expression and proliferation of beta cells |
| title_full | TMEM219 regulates the transcription factor expression and proliferation of beta cells |
| title_fullStr | TMEM219 regulates the transcription factor expression and proliferation of beta cells |
| title_full_unstemmed | TMEM219 regulates the transcription factor expression and proliferation of beta cells |
| title_short | TMEM219 regulates the transcription factor expression and proliferation of beta cells |
| title_sort | tmem219 regulates the transcription factor expression and proliferation of beta cells |
| topic | type 1 diabetes endocrine progenitors TMEM219 IGFBP3 islets mature and immature beta cells |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2024.1306127/full |
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