SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating β-catenin
Mesenchymal stem cells (MSCs) are multi‐potent cells that can differentiate into osteoblasts, adipocytes, chondrocytes and myocytes. This potential declines with aging. We investigated whether the sirtuin SIRT1 had a function in MSCs by creating MSC specific SIRT1 knock‐out (MSCKO) mice. Aged MSCKO...
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| Format: | Article |
| Language: | en_US |
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Wiley Blackwell
2014
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| Online Access: | http://hdl.handle.net/1721.1/84504 https://orcid.org/0000-0003-4064-2510 |
| _version_ | 1826201958710509568 |
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| author | Simic, Petra Zainabadi, Kayvan Sykes, David B. Saez, Borja Lotinun, Sutada Baron, Roland Scadden, David Schipani, Ernestina Bell, Eric L. Guarente, Leonard Pershing |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Simic, Petra Zainabadi, Kayvan Sykes, David B. Saez, Borja Lotinun, Sutada Baron, Roland Scadden, David Schipani, Ernestina Bell, Eric L. Guarente, Leonard Pershing |
| author_sort | Simic, Petra |
| collection | MIT |
| description | Mesenchymal stem cells (MSCs) are multi‐potent cells that can differentiate into osteoblasts, adipocytes, chondrocytes and myocytes. This potential declines with aging. We investigated whether the sirtuin SIRT1 had a function in MSCs by creating MSC specific SIRT1 knock‐out (MSCKO) mice. Aged MSCKO mice (2.2 years old) showed defects in tissues derived from MSCs; i.e. a reduction in subcutaneous fat, cortical bone thickness and trabecular volume. Young mice showed related but less pronounced effects. MSCs isolated from MSCKO mice showed reduced differentiation towards osteoblasts and chondrocytes in vitro, but no difference in proliferation or apoptosis. Expression of β‐catenin targets important for differentiation was reduced in MSCKO cells. Moreover, while β‐catenin itself (T41A mutant resistant to cytosolic turnover) accumulated in the nuclei of wild‐type MSCs, it was unable to do so in MSCKO cells. However, mutating K49R or K345R in β‐catenin to mimic deacetylation restored nuclear localization and differentiation potential in MSCKO cells. We conclude that SIRT1 deacetylates β‐catenin to promote its accumulation in the nucleus leading to transcription of genes for MSC differentiation. |
| first_indexed | 2024-09-23T11:59:41Z |
| format | Article |
| id | mit-1721.1/84504 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:59:41Z |
| publishDate | 2014 |
| publisher | Wiley Blackwell |
| record_format | dspace |
| spelling | mit-1721.1/845042022-09-27T23:19:22Z SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating β-catenin Simic, Petra Zainabadi, Kayvan Sykes, David B. Saez, Borja Lotinun, Sutada Baron, Roland Scadden, David Schipani, Ernestina Bell, Eric L. Guarente, Leonard Pershing Massachusetts Institute of Technology. Department of Biology Paul F. Glenn Center for Biology of Aging Research (Massachusetts Institute of Technology) Simic, Petra Zainabadi, Kayvan Bell, Eric L. Guarente, Leonard Pershing Mesenchymal stem cells (MSCs) are multi‐potent cells that can differentiate into osteoblasts, adipocytes, chondrocytes and myocytes. This potential declines with aging. We investigated whether the sirtuin SIRT1 had a function in MSCs by creating MSC specific SIRT1 knock‐out (MSCKO) mice. Aged MSCKO mice (2.2 years old) showed defects in tissues derived from MSCs; i.e. a reduction in subcutaneous fat, cortical bone thickness and trabecular volume. Young mice showed related but less pronounced effects. MSCs isolated from MSCKO mice showed reduced differentiation towards osteoblasts and chondrocytes in vitro, but no difference in proliferation or apoptosis. Expression of β‐catenin targets important for differentiation was reduced in MSCKO cells. Moreover, while β‐catenin itself (T41A mutant resistant to cytosolic turnover) accumulated in the nuclei of wild‐type MSCs, it was unable to do so in MSCKO cells. However, mutating K49R or K345R in β‐catenin to mimic deacetylation restored nuclear localization and differentiation potential in MSCKO cells. We conclude that SIRT1 deacetylates β‐catenin to promote its accumulation in the nucleus leading to transcription of genes for MSC differentiation. Fulbright Program (Postdoctoral Fellowship) F32 CA 132358 National Institutes of Health (U.S.) Paul F. Glenn Foundation 2014-01-24T17:40:34Z 2014-01-24T17:40:34Z 2013-01 2012-11 Article http://purl.org/eprint/type/JournalArticle 17574676 1757-4684 http://hdl.handle.net/1721.1/84504 Simic, Petra, Kayvan Zainabadi, Eric Bell, David B. Sykes, Borja Saez, Sutada Lotinun, Roland Baron, David Scadden, Ernestina Schipani, and Leonard Guarente. “SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating β-catenin.” EMBO Molecular Medicine 5, no. 3 (March 30, 2013): 430-440. https://orcid.org/0000-0003-4064-2510 en_US http://dx.doi.org/10.1002/emmm.201201606 EMBO Molecular Medicine Creative Commons Attribution http://creativecommons.org/licenses/by/3.0/ application/pdf Wiley Blackwell European Molecular Biology Organization (EMBO) |
| spellingShingle | Simic, Petra Zainabadi, Kayvan Sykes, David B. Saez, Borja Lotinun, Sutada Baron, Roland Scadden, David Schipani, Ernestina Bell, Eric L. Guarente, Leonard Pershing SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating β-catenin |
| title | SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating β-catenin |
| title_full | SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating β-catenin |
| title_fullStr | SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating β-catenin |
| title_full_unstemmed | SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating β-catenin |
| title_short | SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating β-catenin |
| title_sort | sirt1 regulates differentiation of mesenchymal stem cells by deacetylating β catenin |
| url | http://hdl.handle.net/1721.1/84504 https://orcid.org/0000-0003-4064-2510 |
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