Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway
Dysfunction or death of pancreatic β cells underlies both types of diabetes. This functional decline begins with β cell stress and de-differentiation. Current drugs for type 2 diabetes (T2D) lower blood glucose levels but they do not directly alleviate β cell stress nor prevent, let alone reverse, β...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2014-09-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/02809 |
| _version_ | 1811253299128565760 |
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| author | Barak Blum Adam N Roose Ornella Barrandon René Maehr Anthony C Arvanites Lance S Davidow Jeffrey C Davis Quinn P Peterson Lee L Rubin Douglas A Melton |
| author_facet | Barak Blum Adam N Roose Ornella Barrandon René Maehr Anthony C Arvanites Lance S Davidow Jeffrey C Davis Quinn P Peterson Lee L Rubin Douglas A Melton |
| author_sort | Barak Blum |
| collection | DOAJ |
| description | Dysfunction or death of pancreatic β cells underlies both types of diabetes. This functional decline begins with β cell stress and de-differentiation. Current drugs for type 2 diabetes (T2D) lower blood glucose levels but they do not directly alleviate β cell stress nor prevent, let alone reverse, β cell de-differentiation. We show here that Urocortin 3 (Ucn3), a marker for mature β cells, is down-regulated in the early stages of T2D in mice and when β cells are stressed in vitro. Using an insulin expression-coupled lineage tracer, with Ucn3 as a reporter for the mature β cell state, we screen for factors that reverse β cell de-differentiation. We find that a small molecule inhibitor of TGFβ receptor I (Alk5) protects cells from the loss of key β cell transcription factors and restores a mature β cell identity even after exposure to prolonged and severe diabetes. |
| first_indexed | 2024-04-12T16:48:47Z |
| format | Article |
| id | doaj.art-3ad5b45b82e84774b6e71116e7e9164d |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:48:47Z |
| publishDate | 2014-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3ad5b45b82e84774b6e71116e7e9164d2022-12-22T03:24:28ZengeLife Sciences Publications LtdeLife2050-084X2014-09-01310.7554/eLife.02809Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathwayBarak Blum0Adam N Roose1Ornella Barrandon2René Maehr3Anthony C Arvanites4Lance S Davidow5Jeffrey C Davis6Quinn P Peterson7Lee L Rubin8Douglas A Melton9Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United StatesDepartment of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United StatesDepartment of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United StatesDepartment of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United StatesDepartment of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United StatesDepartment of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United StatesDepartment of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United StatesDepartment of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United StatesDepartment of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United StatesDepartment of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States; Howard Hughes Medical Institute, Harvard University, Cambridge, United StatesDysfunction or death of pancreatic β cells underlies both types of diabetes. This functional decline begins with β cell stress and de-differentiation. Current drugs for type 2 diabetes (T2D) lower blood glucose levels but they do not directly alleviate β cell stress nor prevent, let alone reverse, β cell de-differentiation. We show here that Urocortin 3 (Ucn3), a marker for mature β cells, is down-regulated in the early stages of T2D in mice and when β cells are stressed in vitro. Using an insulin expression-coupled lineage tracer, with Ucn3 as a reporter for the mature β cell state, we screen for factors that reverse β cell de-differentiation. We find that a small molecule inhibitor of TGFβ receptor I (Alk5) protects cells from the loss of key β cell transcription factors and restores a mature β cell identity even after exposure to prolonged and severe diabetes.https://elifesciences.org/articles/02809beta celldedifferentiationdiabetesAlk5 inhibitor IIUcn3Tgf-beta |
| spellingShingle | Barak Blum Adam N Roose Ornella Barrandon René Maehr Anthony C Arvanites Lance S Davidow Jeffrey C Davis Quinn P Peterson Lee L Rubin Douglas A Melton Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway eLife beta cell dedifferentiation diabetes Alk5 inhibitor II Ucn3 Tgf-beta |
| title | Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway |
| title_full | Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway |
| title_fullStr | Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway |
| title_full_unstemmed | Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway |
| title_short | Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway |
| title_sort | reversal of β cell de differentiation by a small molecule inhibitor of the tgfβ pathway |
| topic | beta cell dedifferentiation diabetes Alk5 inhibitor II Ucn3 Tgf-beta |
| url | https://elifesciences.org/articles/02809 |
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