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      Aged iPSCs display an uncommon mitochondrial appearance and fail to undergo in vitro neurogenesis

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          Abstract

          Reprogramming of human fibroblasts into induced pluripotent stem cells (iPSCs) leads to mitochondrial rejuvenation, making iPSCs a candidate model to study the mitochondrial biology during stemness and differentiation. At present, it is generally accepted that iPSCs can be maintained and propagated indefinitely in culture, but no specific studies have addressed this issue. In our study, we investigated features related to the 'biological age' of iPSCs, culturing and analyzing iPSCs kept for prolonged periods in vitro. We have demonstrated that aged iPSCs present an increased number of mitochondria per cell with an altered mitochondrial membrane potential and fail to properly undergo in vitro neurogenesis. In aged iPSCs we have also found an altered expression of genes relevant to mitochondria biogenesis. Overall, our results shed light on the mitochondrial biology of young and aged iPSCs and explore how an altered mitochondrial status may influence neuronal differentiation. Our work suggests to deepen the understanding of the iPSCs biology before considering their use in clinical applications.

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          Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution.

          Nimet Maherali, Rupa Sridharan, Wei Xie … (2007)
          Ectopic expression of the four transcription factors Oct4, Sox2, c-Myc, and Klf4 is sufficient to confer a pluripotent state upon the fibroblast genome, generating induced pluripotent stem (iPS) cells. It remains unknown if nuclear reprogramming induced by these four factors globally resets epigenetic differences between differentiated and pluripotent cells. Here, using novel selection approaches, we have generated iPS cells from fibroblasts to characterize their epigenetic state. Female iPS cells showed reactivation of a somatically silenced X chromosome and underwent random X inactivation upon differentiation. Genome-wide analysis of two key histone modifications indicated that iPS cells are highly similar to ES cells. Consistent with these observations, iPS cells gave rise to viable high-degree chimeras with contribution to the germline. These data show that transcription factor-induced reprogramming leads to the global reversion of the somatic epigenome into an ES-like state. Our results provide a paradigm for studying the epigenetic modifications that accompany nuclear reprogramming and suggest that abnormal epigenetic reprogramming does not pose a problem for the potential therapeutic applications of iPS cells.
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            Stem cell aging: mechanisms, regulators and therapeutic opportunities.

            Juhyun Oh, Yang Lee, Amy J. Wagers (2014)
            Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both supporting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic 'memory' that is indelibly written or one that can be reset.
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              Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state.

              L Lapasset, O Milhavet, A. Prieur … (2011)
              Direct reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) provides a unique opportunity to derive patient-specific stem cells with potential applications in tissue replacement therapies and without the ethical concerns of human embryonic stem cells (hESCs). However, cellular senescence, which contributes to aging and restricted longevity, has been described as a barrier to the derivation of iPSCs. Here we demonstrate, using an optimized protocol, that cellular senescence is not a limit to reprogramming and that age-related cellular physiology is reversible. Thus, we show that our iPSCs generated from senescent and centenarian cells have reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism, and are indistinguishable from hESCs. Finally, we show that senescent and centenarian-derived pluripotent stem cells are able to redifferentiate into fully rejuvenated cells. These results provide new insights into iPSC technology and pave the way for regenerative medicine for aged patients.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Aging (Albany NY)
                Journal ID (iso-abbrev): Aging (Albany NY)
                Journal ID (publisher-id): ImpactJ
                Title: Aging (Albany NY)
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1945-4589
                Publication date Collection: December 2014
                Publication date (Electronic): 30 December 2014
                Volume: 6
                Issue: 12
                Pages: 1094-1108
                Affiliations
                1 Gene Expression–Microarrays Laboratory, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy
                2 Confocal Microscopy Core Facility, Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome 00165, Italy
                3 Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Department of Neurosciences, Bambino Gesù Children's Research Hospital, IRCCS, Piazza S. Onofrio, 4 00165 Rome, Italy
                Author notes
                Article
                DOI: 10.18632/aging.100708
                PMC ID: 4298368
                PubMed ID: 25567319
                SO-VID: b8799af3-abc0-437d-ade1-466891ffd08c
                Copyright © Copyright: © 2014 Masotti et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                Date received : 5 September 2014
                Date accepted : 20 December 2014
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Cell biology
                Keywords: induced pluripotent stem cells,mitochondria,stem cell aging,mitochondrial dysfunction,in vitro neurogenesis
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: induced pluripotent stem cells, mitochondria, stem cell aging, mitochondrial dysfunction, in vitro neurogenesis

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