Journal
AGING-US
Volume 4, Issue 1, Pages 60-73Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.100428
Keywords
rejuvenation; electron microscopy; disease modeling; INK4/ARF locus; caspase; GPX1; PDX1
Categories
Funding
- Mayo Clinic
- Marriott Individualized Medicine Award
- Marriot Foundation
- Eisenberg Stem Cell Trust
- Bernard and Edith Waterman Pilot Grants
- Minnesota Partnership Grant
- Marriott Specialized Workforce Development Award in Individualized Medicine
- Robert and Arlene Kogod Center on Aging
- National Institutes of Health [HL083439, DK085516]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL083439] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK085516] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM072474] Funding Source: NIH RePORTER
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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 p15(INK4b)/p16(INK4a) 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.
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