Reprogrammed keratinocytes from elderly type 2 diabetes patients suppress senescence genes to acquire induced pluripotency.
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.
Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Seiga
S
Ohmine
Karen A
KA
Squillace
Katherine A
KA
Hartjes
Michael C
MC
Deeds
Adam S
AS
Armstrong
Tayaramma
T
Thatava
Toshie
T
Sakuma
Andre
A
Terzic
Yogish
Y
Kudva
Yasuhiro
Y
Ikeda
D000368:Aged; D000375:Aging / Q000235:genetics*; D018929:Cell Culture Techniques; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D016678:Genome; D006801:Humans; D007328:Insulin / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology* / Q000502:physiology*; D000090062:Kruppel-Like Factor 4; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D015398:Signal Transduction
D007328:Insulin; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4