1. Aged induced pluripotent stem cell (iPSCs) as a new cellular model for studying premature aging.
- Author
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Petrini S, Borghi R, D'Oria V, Restaldi F, Moreno S, Novelli A, Bertini E, and Compagnucci C
- Subjects
- Actin Cytoskeleton metabolism, Age Factors, Aging genetics, Aging metabolism, Aging, Premature genetics, Aging, Premature metabolism, Cell Line, Humans, Induced Pluripotent Stem Cells metabolism, Lamin Type A genetics, Lamin Type A metabolism, Lamin Type B genetics, Lamin Type B metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Microfilament Proteins genetics, Microfilament Proteins metabolism, NF-kappa B metabolism, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Nuclear Envelope metabolism, Nuclear Envelope pathology, Nuclear Proteins genetics, Nuclear Proteins metabolism, Phenotype, Signal Transduction, Sirtuins genetics, Sirtuins metabolism, Time Factors, Trans-Activators metabolism, Aging pathology, Aging, Premature pathology, Cellular Senescence, Induced Pluripotent Stem Cells pathology
- Abstract
Nuclear integrity and mechanical stability of the nuclear envelope (NE) are conferred by the nuclear lamina, a meshwork of intermediate filaments composed of A- and B-type lamins, supporting the inner nuclear membrane and playing a pivotal role in chromatin organization and epigenetic regulation. During cell senescence, nuclear alterations also involving NE architecture are widely described. In the present study, we utilized induced pluripotent stem cells (iPSCs) upon prolonged in vitro culture as a model to study aging and investigated the organization and expression pattern of NE major constituents. Confocal and four-dimensional imaging combined with molecular analyses, showed that aged iPSCs are characterized by nuclear dysmorphisms, nucleoskeletal components (lamin A/C-prelamin isoforms, lamin B1, emerin, and nesprin-2) imbalance, leading to impaired nucleo-cytoplasmic MKL1 shuttling, actin polymerization defects, mitochondrial dysfunctions, SIRT7 downregulation and NF-kBp65 hyperactivation. The observed age-related NE features of iPSCs closely resemble those reported for premature aging syndromes (e.g., Hutchinson-Gilford progeria syndrome) and for somatic cell senescence. These findings validate the use of aged iPSCs as a suitable cellular model to study senescence and for investigating therapeutic strategies aimed to treat premature aging.
- Published
- 2017
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