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.
Highlights
Over 200 million people worldwide, ranging from 20 to 79 years in age, suffer from diabetes mellitus, typically the late onset type 2 diabetes (T2D) [1, 2]
We examined the feasibility of induced pluripotent stem (iPS) derivation from epidermal keratinocytes from elderly T2D patients, analyzed molecular and cellular events associated with nuclear reprogramming, and determined differentiation propensities of derived pluripotent cells
The present study reports derivation of iPS cells from T2D patients
Summary
Over 200 million people worldwide, ranging from 20 to 79 years in age, suffer from diabetes mellitus, typically the late onset type 2 diabetes (T2D) [1, 2]. By 2025, this number is projected to rise to over 300 million propelled by the aging of the population. Competent for multilineage differentiation, embryonic stem (ES) cells are regarded potentially promising for regenerative applications. Differentiation of ES cells into transplantable tissues could lead to repair therapies for severe degenerative diseases, including diabetes. Established nuclear reprogramming methodologies allow generation of autologous pluripotent stem cells from somatic sources. Ectopic expression of primordial transcription factors [6,7,8,9,10] dedifferentiates adult somatic tissue into induced pluripotent stem (iPS) cells. IPS cells share similar properties with ES cells with respect to morphology, growth, www.impactaging.com
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