Aged induced pluripotent stem cell (iPSCs) as a new cellular model for studying premature aging

Aging (Albany NY). 2017 May 31;9(5):1453-1469. doi: 10.18632/aging.101248.

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.

Keywords: MKL1; SIRT7; actin cytoskeleton; emerin; induced pluripotent stem cells; lamins; mitochondria; nesprins; nucleoskeleton.

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Age Factors
  • Aging / genetics
  • Aging / metabolism
  • Aging / pathology*
  • Aging, Premature / genetics
  • Aging, Premature / metabolism
  • Aging, Premature / pathology*
  • Cell Line
  • Cellular Senescence*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology*
  • 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

Substances

  • LMNA protein, human
  • Lamin Type A
  • Lamin Type B
  • MRTFA protein, human
  • Membrane Proteins
  • Microfilament Proteins
  • NF-kappa B
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • SIRT7 protein, human
  • SYNE2 protein, human
  • Trans-Activators
  • emerin
  • prelamin A
  • Sirtuins