Reprogrammed keratinocytes from elderly type 2 diabetes patients suppress senescence genes to acquire induced pluripotency

Seiga Ohmine, Karen A. Squillace, Katherine A. Hartjes, Michael C. Deeds, Adam S. Armstrong, Tayaramma Thatava, Toshie Sakuma, Andre Terzic, Yogish Kudva, Yasuhiro Ikeda

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Nuclear reprogramming enables patient-specific derivation of induced pluripotent stem (iPS) cells from adult tissue. Yet, iPS generation from patients with type 2 diabetes (T2D) has not been demonstrated. Here, we report reproducible iPS derivation of epidermal keratinocytes (HK) from elderly T2D patients. Transduced with human OCT4, SOX2, KLF4 and c-MYC stemness factors under serum-free and feeder-free conditions, reprogrammed cells underwent dedifferentiation with mitochondrial restructuring, induction of endogenous pluripotency genes - including NANOG, LIN28, and TERT, and down-regulation of cytoskeletal, MHC class I- and apoptosis-related genes. Notably, derived iPS clones acquired a rejuvenated state, characterized by elongated telomeres and suppressed senescence-related p15INK4b/p16INK4a gene expression and oxidative stress signaling. Stepwise guidance with lineage-specifying factors, including Indolactam V and GLP-1, redifferentiated HK-derived iPS clones into insulin-producing islet-like progeny. Thus, in elderly T2D patients, reprogramming of keratinocytes ensures a senescence-privileged status yielding iPS cells proficient for regenerative applications.

Original languageEnglish (US)
Pages (from-to)60-73
Number of pages14
JournalAging
Volume4
Issue number1
DOIs
StatePublished - Jan 2012

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Keywords

  • Caspase
  • Disease modeling
  • Electron microscopy
  • GPX1
  • INK4/ARF locus
  • PDX1
  • Rejuvenation

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Ohmine, S., Squillace, K. A., Hartjes, K. A., Deeds, M. C., Armstrong, A. S., Thatava, T., Sakuma, T., Terzic, A., Kudva, Y., & Ikeda, Y. (2012). Reprogrammed keratinocytes from elderly type 2 diabetes patients suppress senescence genes to acquire induced pluripotency. Aging, 4(1), 60-73. https://doi.org/10.18632/aging.100428