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Aging Cell. 2017 Aug;16(4):870-887. doi: 10.1111/acel.12621. Epub 2017 Jun 8.

Reprogramming progeria fibroblasts re-establishes a normal epigenetic landscape.

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The Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, K1H 8L6.
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Pacific Northwest Diabetes Research Institute, 720 Broadway, Seattle, WA, 98103, USA.
Cross Cancer Institute and the Department of Experimental Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada, T6G 1Z2.
Ottawa Bioinformatics Core Facility, The Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, K1H 8L6.
Department of Chemical Engineering, University of Toronto, Toronto, Ontario, Canada.
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Pathology and Experimental Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
Ottawa Institute of Systems Biology, Ottawa, Ontario, Canada.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.


Ideally, disease modeling using patient-derived induced pluripotent stem cells (iPSCs) enables analysis of disease initiation and progression. This requires any pathological features of the patient cells used for reprogramming to be eliminated during iPSC generation. Hutchinson-Gilford progeria syndrome (HGPS) is a segmental premature aging disorder caused by the accumulation of the truncated form of Lamin A known as Progerin within the nuclear lamina. Cellular hallmarks of HGPS include nuclear blebbing, loss of peripheral heterochromatin, defective epigenetic inheritance, altered gene expression, and senescence. To model HGPS using iPSCs, detailed genome-wide and structural analysis of the epigenetic landscape is required to assess the initiation and progression of the disease. We generated a library of iPSC lines from fibroblasts of patients with HGPS and controls, including one family trio. HGPS patient-derived iPSCs are nearly indistinguishable from controls in terms of pluripotency, nuclear membrane integrity, as well as transcriptional and epigenetic profiles, and can differentiate into affected cell lineages recapitulating disease progression, despite the nuclear aberrations, altered gene expression, and epigenetic landscape inherent to the donor fibroblasts. These analyses demonstrate the power of iPSC reprogramming to reset the epigenetic landscape to a revitalized pluripotent state in the face of widespread epigenetic defects, validating their use to model the initiation and progression of disease in affected cell lineages.


Lamin A; aging; epigenetics; induced pluripotent stem cells; lamina; progeria; reprogramming

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