Reprogrammed keratinocytes from elderly type 2 diabetes patients suppress senescence genes to acquire induced pluripotency
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.
Introduction
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. Thus, new treatments for T2D, including approaches to address progressive pancreatic beta cell insufficiency, are needed.
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. In preclinical studies, human ES cells have been differentiated into insulin-producing cells [3-5], which can reverse the course of diabetes [3]. However, ES cell use is associated with ethical issues and further limited by allogeneic mismatch, restricting clinical application. Recently established nuclear reprogramming methodologies allow generation of autologous pluripotent stem cells from somatic sources. Ectopic expression of primordial transcription factors [6-10] dedifferentiates adult somatic tissue into induced pluripotent stem (iPS) cells. In general, iPS cells share similar properties with ES cells with respect to morphology, growth, expression of pluripotency-associated factors, self-renewal and multilineage potential [11]. Analysis of global gene expression profiles of human iPS cells has also revealed patterns similar to those of human ES cells, with notable upregulation of pluripotency-associated genes [12, 13]. Similar to ES cells, human iPS cells can be induced to differentiate into various cell types, including insulin-producing cells [14-17], as well as tissues associated with T2D complications such as neurons [18] and heart muscle [19-21]. Diverse somatic sources have been successfully reprogramed, including fibroblasts, stomach and liver cell cultures [22], and blood cells including mature B and T lymphocytes [23]. Moreover, human keratinocytes [24, 25] are a promising resource for clinical-grade iPS derivation. Indeed, efficient and rapid iPS derivation from keratinocytes has been demonstrated from a 4 year-old child and 28-35 year-old young adults [25]. Disease-specific iPS derivation has been also reported from young adults with various genetic or degenerative diseases, including generation of iPS cells from type 1 diabetes (T1D) [14, 26]. However, to date, derivation of iPS cells from T2D patients has not been documented. Moreover, it remains uncertain whether advanced age compromises cellular reprogramming.
Here, we examined the feasibility of 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. Keratinocytes from T2D patients offered a reproducible source for patient-specific iPS generation, proficient in yielding insulin-producing islet-like progeny, through suppressed senescence-related pathways. https://www.aging-us.com/article/100428/text
When public mention today’s medicine, precision plays one of the most important roles and people’s lives are directly dependent on it. Likewise, any researches pertaining to medicine are required to meet the highest standards. The challenge nowadays is that any recommendations of researches can be posted online and used as a reference without being adequately verified and approved. Mikhail (Misha) Blagosklonny of Oncotarget perfectly understood this problem and attempted to come up with an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been founded back in 2010. The key principle of this journal is related to Altmetric scores that are used as a quality measure. That helps both readers and authors to validate publications with Altmetric Article Reports that create “real-time feedback containing data summary related to a particular publication.” Oncotarget website has a complete publications list with corresponding scores higher than 100 as well as reports mentioned previously. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it provides the necessary help to anyone, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This article was published back in 2018 by Oncotarget and completed by diversified experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study mentions that “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and provides an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The article has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that majority of readers are aiming to comprehend the very meaning of it. Based on the Altmetric website, the score relates to “how many people have been exposed to and engaged with a scholarly output.” Hence, the paper about melanoma, was used for citations in various news articles 69 times. Moreover, it was referred to in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their news on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study
Another Oncotarget’s study with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This research has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have come across a concise overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do receive helpful scientific facts. Oncotarget is happy to have the ability to share with online viewers this highly appreciated and top-quality information, that is trustworthy and reliable.
When people refer to modern medicine, accuracy plays one of the most crucial roles and people’s lives are literally dependent on it. Hence, any researches related to medicine are required to comply with the top standards. The challenge today is that any outcomes of researches can be shared online and used as a reference without being precisely verified and approved. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this challenge and tried to generate an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been established back in 2010. The key principle of this journal is based on Altmetric scores that are used as a quality indicator. That helps both readers and authors to validate publications with Altmetric Article Reports that create “real-time feedback containing data summary related to a particular publication.” Oncotarget website demonstrates a complete publications list with respective scores higher than 100 as well as reports mentioned above. Mikhail (Misha) Blagosklonny glad to share his new approach and hopes it creates the required help to anybody, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This study was released back in 2018 by Oncotarget and completed by diversified experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study mentions that “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The publication has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that most of readers are aiming to comprehend the very meaning of it. Based on the Altmetric website, the score indicates “how many people have been exposed to and engaged with a scholarly output.” Hereby, the article about melanoma, was used for citations in different news articles 69 times. Moreover, it was quoted in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their news on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study
Another Oncotarget’s research with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This article has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have seen a brief overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do get useful scientific facts. Oncotarget is glad to have the ability to share with online readers this highly appreciated and top-quality information, that is trustworthy and reliable.
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