Impact of Combined Baricitinib and FTI Treatment on Adipogenesis in Hutchinson–Gilford Progeria Syndrome and Other Lipodystrophic Laminopathies
Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disease that causes premature aging symptoms, such as vascular diseases, lipodystrophy, loss of bone mineral density, and alopecia. HGPS is mostly linked to a heterozygous and de novo mutation in the LMNA gene (c.1824 C > T; p.G608G),...
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MDPI AG
2023-05-01
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| Online Access: | https://www.mdpi.com/2073-4409/12/10/1350 |
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| author | Ramona Hartinger Eva-Maria Lederer Elisa Schena Giovanna Lattanzi Karima Djabali |
| author_facet | Ramona Hartinger Eva-Maria Lederer Elisa Schena Giovanna Lattanzi Karima Djabali |
| author_sort | Ramona Hartinger |
| collection | DOAJ |
| description | Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disease that causes premature aging symptoms, such as vascular diseases, lipodystrophy, loss of bone mineral density, and alopecia. HGPS is mostly linked to a heterozygous and de novo mutation in the LMNA gene (c.1824 C > T; p.G608G), resulting in the production of a truncated prelamin A protein called “progerin”. Progerin accumulation causes nuclear dysfunction, premature senescence, and apoptosis. Here, we examined the effects of baricitinib (Bar), an FDA-approved JAK/STAT inhibitor, and a combination of Bar and lonafarnib (FTI) treatment on adipogenesis using skin-derived precursors (SKPs). We analyzed the effect of these treatments on the differentiation potential of SKPs isolated from pre-established human primary fibroblast cultures. Compared to mock-treated HGPS SKPs, Bar and Bar + FTI treatments improved the differentiation of HGPS SKPs into adipocytes and lipid droplet formation. Similarly, Bar and Bar + FTI treatments improved the differentiation of SKPs derived from patients with two other lipodystrophic diseases: familial partial lipodystrophy type 2 (FPLD2) and mandibuloacral dysplasia type B (MADB). Overall, the results show that Bar treatment improves adipogenesis and lipid droplet formation in HGPS, FPLD2, and MADB, indicating that Bar + FTI treatment might further ameliorate HGPS pathologies compared to lonafarnib treatment alone. |
| first_indexed | 2024-03-11T03:52:12Z |
| format | Article |
| id | doaj.art-e3724645a7124f78914ec85e8119eb8e |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T03:52:12Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-e3724645a7124f78914ec85e8119eb8e2023-11-18T00:52:18ZengMDPI AGCells2073-44092023-05-011210135010.3390/cells12101350Impact of Combined Baricitinib and FTI Treatment on Adipogenesis in Hutchinson–Gilford Progeria Syndrome and Other Lipodystrophic LaminopathiesRamona Hartinger0Eva-Maria Lederer1Elisa Schena2Giovanna Lattanzi3Karima Djabali4Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, GermanyEpigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, GermanyUnit of Bologna, CNR Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, 40136 Bologna, ItalyUnit of Bologna, CNR Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, 40136 Bologna, ItalyEpigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, GermanyHutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disease that causes premature aging symptoms, such as vascular diseases, lipodystrophy, loss of bone mineral density, and alopecia. HGPS is mostly linked to a heterozygous and de novo mutation in the LMNA gene (c.1824 C > T; p.G608G), resulting in the production of a truncated prelamin A protein called “progerin”. Progerin accumulation causes nuclear dysfunction, premature senescence, and apoptosis. Here, we examined the effects of baricitinib (Bar), an FDA-approved JAK/STAT inhibitor, and a combination of Bar and lonafarnib (FTI) treatment on adipogenesis using skin-derived precursors (SKPs). We analyzed the effect of these treatments on the differentiation potential of SKPs isolated from pre-established human primary fibroblast cultures. Compared to mock-treated HGPS SKPs, Bar and Bar + FTI treatments improved the differentiation of HGPS SKPs into adipocytes and lipid droplet formation. Similarly, Bar and Bar + FTI treatments improved the differentiation of SKPs derived from patients with two other lipodystrophic diseases: familial partial lipodystrophy type 2 (FPLD2) and mandibuloacral dysplasia type B (MADB). Overall, the results show that Bar treatment improves adipogenesis and lipid droplet formation in HGPS, FPLD2, and MADB, indicating that Bar + FTI treatment might further ameliorate HGPS pathologies compared to lonafarnib treatment alone.https://www.mdpi.com/2073-4409/12/10/1350progerinlonafarnibbaricitiniblamin Aadipogenesisprogeria |
| spellingShingle | Ramona Hartinger Eva-Maria Lederer Elisa Schena Giovanna Lattanzi Karima Djabali Impact of Combined Baricitinib and FTI Treatment on Adipogenesis in Hutchinson–Gilford Progeria Syndrome and Other Lipodystrophic Laminopathies Cells progerin lonafarnib baricitinib lamin A adipogenesis progeria |
| title | Impact of Combined Baricitinib and FTI Treatment on Adipogenesis in Hutchinson–Gilford Progeria Syndrome and Other Lipodystrophic Laminopathies |
| title_full | Impact of Combined Baricitinib and FTI Treatment on Adipogenesis in Hutchinson–Gilford Progeria Syndrome and Other Lipodystrophic Laminopathies |
| title_fullStr | Impact of Combined Baricitinib and FTI Treatment on Adipogenesis in Hutchinson–Gilford Progeria Syndrome and Other Lipodystrophic Laminopathies |
| title_full_unstemmed | Impact of Combined Baricitinib and FTI Treatment on Adipogenesis in Hutchinson–Gilford Progeria Syndrome and Other Lipodystrophic Laminopathies |
| title_short | Impact of Combined Baricitinib and FTI Treatment on Adipogenesis in Hutchinson–Gilford Progeria Syndrome and Other Lipodystrophic Laminopathies |
| title_sort | impact of combined baricitinib and fti treatment on adipogenesis in hutchinson gilford progeria syndrome and other lipodystrophic laminopathies |
| topic | progerin lonafarnib baricitinib lamin A adipogenesis progeria |
| url | https://www.mdpi.com/2073-4409/12/10/1350 |
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