Zeitschriftenartikel: „Functional reprogramming“

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Trakala, Marianna, Sara Rodríguez-Acebes, María Maroto, Catherine E. Symonds, David Santamaría, Sagrario Ortega, Mariano Barbacid, Juan Méndez und Marcos Malumbres. „Functional Reprogramming of Polyploidization in Megakaryocytes“. Developmental Cell 32, Nr. 2 (Januar 2015): 155–67. http://dx.doi.org/10.1016/j.devcel.2014.12.015.

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Kubatiev, A. A., und A. A. Pal'tsyn. „INTRACELLULAR BRAIN REGENERATION: A NEW VIEW“. Annals of the Russian academy of medical sciences 67, Nr. 8 (11.08.2012): 21–25. http://dx.doi.org/10.15690/vramn.v67i8.345.

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Mechanism of neuron regeneration in the cortex was discovered. Heterokaryon, a cell with two distinct nuclei, is formed by the fusion of neuron with oligodendrocyte. We showed that oligodendrocyte nucleus in heterokaryons is exposed to neuron-specific reprogramming. Oligodendrocyte nucleus becomes similar to neuron nucleus and in result of reprogramming is undefined from it according to morphology (size, shape, chromatin structure). Reprogrammed oligodendrocyte nuclei begin to express the neural specific markers NeuN and MAP2. Rate of transcription in the oligodendrocyte nuclei increases as in neurons. After completion of neuron-specific reprogrammin, second nucleus appears in neuron which increases the functional capacity of the cell. We present evidence that this process is the basis of physiological and reparative regeneration of the brain.

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Kumar, Satish, Joanne E. Curran, David C. Glahn und John Blangero. „Utility of Lymphoblastoid Cell Lines for Induced Pluripotent Stem Cell Generation“. Stem Cells International 2016 (2016): 1–20. http://dx.doi.org/10.1155/2016/2349261.

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A large number of EBV immortalized LCLs have been generated and maintained in genetic/epidemiological studies as a perpetual source of DNA and as a surrogatein vitrocell model. Recent successes in reprograming LCLs into iPSCs have paved the way for generating more relevantin vitrodisease models using this existing bioresource. However, the overall reprogramming efficiency and success rate remain poor and very little is known about the mechanistic changes that take place at the transcriptome and cellular functional level during LCL-to-iPSC reprogramming. Here, we report a new optimized LCL-to-iPSC reprogramming protocol using episomal plasmids encoding pluripotency transcription factors and mouse p53DD (p53 carboxy-terminal dominant-negative fragment) and commercially available reprogramming media. We achieved a consistently high reprogramming efficiency and 100% success rate using this optimized protocol. Further, we investigated the transcriptional changes in mRNA and miRNA levels, using FC-abs ≥ 2.0 and FDR ≤ 0.05 cutoffs; 5,228 mRNAs and 77 miRNAs were differentially expressed during LCL-to-iPSC reprogramming. The functional enrichment analysis of the upregulated genes and activation of human pluripotency pathways in the reprogrammed iPSCs showed that the generated iPSCs possess transcriptional and functional profiles very similar to those of human ESCs.

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Paoletti, Camilla, Carla Divieto und Valeria Chiono. „Impact of Biomaterials on Differentiation and Reprogramming Approaches for the Generation of Functional Cardiomyocytes“. Cells 7, Nr. 9 (21.08.2018): 114. http://dx.doi.org/10.3390/cells7090114.

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The irreversible loss of functional cardiomyocytes (CMs) after myocardial infarction (MI) represents one major barrier to heart regeneration and functional recovery. The combination of different cell sources and different biomaterials have been investigated to generate CMs by differentiation or reprogramming approaches although at low efficiency. This critical review article discusses the role of biomaterial platforms integrating biochemical instructive cues as a tool for the effective generation of functional CMs. The report firstly introduces MI and the main cardiac regenerative medicine strategies under investigation. Then, it describes the main stem cell populations and indirect and direct reprogramming approaches for cardiac regenerative medicine. A third section discusses the main techniques for the characterization of stem cell differentiation and fibroblast reprogramming into CMs. Another section describes the main biomaterials investigated for stem cell differentiation and fibroblast reprogramming into CMs. Finally, a critical analysis of the scientific literature is presented for an efficient generation of functional CMs. The authors underline the need for biomimetic, reproducible and scalable biomaterial platforms and their integration with external physical stimuli in controlled culture microenvironments for the generation of functional CMs.

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Özcan, Ismail, und Baris Tursun. „Identifying Molecular Roadblocks for Transcription Factor-Induced Cellular Reprogramming In Vivo by Using C. elegans as a Model Organism“. Journal of Developmental Biology 11, Nr. 3 (31.08.2023): 37. http://dx.doi.org/10.3390/jdb11030037.

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Generating specialized cell types via cellular transcription factor (TF)-mediated reprogramming has gained high interest in regenerative medicine due to its therapeutic potential to repair tissues and organs damaged by diseases or trauma. Organ dysfunction or improper tissue functioning might be restored by producing functional cells via direct reprogramming, also known as transdifferentiation. Regeneration by converting the identity of available cells in vivo to the desired cell fate could be a strategy for future cell replacement therapies. However, the generation of specific cell types via reprogramming is often restricted due to cell fate-safeguarding mechanisms that limit or even block the reprogramming of the starting cell type. Nevertheless, efficient reprogramming to generate homogeneous cell populations with the required cell type’s proper molecular and functional identity is critical. Incomplete reprogramming will lack therapeutic potential and can be detrimental as partially reprogrammed cells may acquire undesired properties and develop into tumors. Identifying and evaluating molecular barriers will improve reprogramming efficiency to reliably establish the target cell identity. In this review, we summarize how using the nematode C. elegans as an in vivo model organism identified molecular barriers of TF-mediated reprogramming. Notably, many identified molecular factors have a high degree of conservation and were subsequently shown to block TF-induced reprogramming of mammalian cells.

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Kalo, Eric, Scott Read und Golo Ahlenstiel. „Reprogramming—Evolving Path to Functional Surrogate β-Cells“. Cells 11, Nr. 18 (08.09.2022): 2813. http://dx.doi.org/10.3390/cells11182813.

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Numerous cell sources are being explored to replenish functional β-cell mass since the proof-of -concept for cell therapy of diabetes was laid down by transplantation of islets. Many of these cell sources have been shown to possess a degree of plasticity permitting differentiation along new lineages into insulin-secreting β-cells. In this review, we explore emerging reprograming pathways that aim to generate bone fide insulin producing cells. We focus on small molecules and key transcriptional regulators that orchestrate phenotypic conversion and maintenance of engineered cells.

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Peng, Bo, Hui Li und Xuan-Xian Peng. „Functional metabolomics: from biomarker discovery to metabolome reprogramming“. Protein & Cell 6, Nr. 9 (02.07.2015): 628–37. http://dx.doi.org/10.1007/s13238-015-0185-x.

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Tian, E., Guoqiang Sun, Guihua Sun, Jianfei Chao, Peng Ye, Charles Warden, Arthur D. Riggs und Yanhong Shi. „Small-Molecule-Based Lineage Reprogramming Creates Functional Astrocytes“. Cell Reports 16, Nr. 3 (Juli 2016): 781–92. http://dx.doi.org/10.1016/j.celrep.2016.06.042.

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Zhu, Hui, Srilatha Swami, Pinglin Yang, Frederic Shapiro und Joy Y. Wu. „Direct Reprogramming of Mouse Fibroblasts into Functional Osteoblasts“. Journal of Bone and Mineral Research 35, Nr. 4 (30.12.2019): 698–713. http://dx.doi.org/10.1002/jbmr.3929.

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Zhou, Huanyu, Matthew E. Dickson, Min Soo Kim, Rhonda Bassel-Duby und Eric N. Olson. „Akt1/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes“. Proceedings of the National Academy of Sciences 112, Nr. 38 (09.09.2015): 11864–69. http://dx.doi.org/10.1073/pnas.1516237112.

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Conversion of fibroblasts to functional cardiomyocytes represents a potential approach for restoring cardiac function after myocardial injury, but the technique thus far has been slow and inefficient. To improve the efficiency of reprogramming fibroblasts to cardiac-like myocytes (iCMs) by cardiac transcription factors [Gata4, Hand2, Mef2c, and Tbx5 (GHMT)], we screened 192 protein kinases and discovered that Akt/protein kinase B dramatically accelerates and amplifies this process in three different types of fibroblasts (mouse embryo, adult cardiac, and tail tip). Approximately 50% of reprogrammed mouse embryo fibroblasts displayed spontaneous beating after 3 wk of induction by Akt plus GHMT. Furthermore, addition of Akt1 to GHMT evoked a more mature cardiac phenotype for iCMs, as seen by enhanced polynucleation, cellular hypertrophy, gene expression, and metabolic reprogramming. Insulin-like growth factor 1 (IGF1) and phosphoinositol 3-kinase (PI3K) acted upstream of Akt whereas the mitochondrial target of rapamycin complex 1 (mTORC1) and forkhead box o3 (Foxo3a) acted downstream of Akt to influence fibroblast-to-cardiomyocyte reprogramming. These findings provide insights into the molecular basis of cardiac reprogramming and represent an important step toward further application of this technique.

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Zhu, Yanbo, Zi Yan, Ze Tang und Wei Li. „Novel Approaches to Profile Functional Long Noncoding RNAs Associated with Stem Cell Pluripotency“. Current Genomics 21, Nr. 1 (25.03.2020): 37–45. http://dx.doi.org/10.2174/1389202921666200210142840.

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The pluripotent state of stem cells depends on the complicated network orchestrated by thousands of factors and genes. Long noncoding RNAs (lncRNAs) are a class of RNA longer than 200 nt without a protein-coding function. Single-cell sequencing studies have identified hundreds of lncRNAs with dynamic changes in somatic cell reprogramming. Accumulating evidence suggests that they participate in the initiation of reprogramming, maintenance of pluripotency, and developmental processes by cis and/or trans mechanisms. In particular, they may interact with proteins, RNAs, and chromatin modifier complexes to form an intricate pluripotency-associated network. In this review, we focus on recent progress in approaches to profiling functional lncRNAs in somatic cell reprogramming and cell differentiation.

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Sun, Lizhe, Xiaofeng Yang, Zuyi Yuan und Hong Wang. „Metabolic Reprogramming in Immune Response and Tissue Inflammation“. Arteriosclerosis, Thrombosis, and Vascular Biology 40, Nr. 9 (September 2020): 1990–2001. http://dx.doi.org/10.1161/atvbaha.120.314037.

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Innate and adaptive immunity participate in and regulate numerous human diseases. Increasing evidence implies that metabolic reprogramming mediates immune cell functional changes during immune responses. In this review, we present and discuss our current understanding of metabolic regulation in different immune cells and their subsets in response to pathological stimuli. An interactive biochemical and molecular model was established to characterize metabolic reprogramming and their functional implication in anti-inflammatory, immune resolution, and proinflammatory responses. We summarize 2 major features of metabolic reprogramming in inflammatory stages in innate and adaptive immune cells: (1) energy production and biosynthesis reprogramming, including increased glycolysis and decreased oxidative phosphorylation, to secure faster ATP production and biosynthesis for defense response and damage repair and (2) epigenetic reprogramming, including enhanced histone acetylation and suppressed DNA methylation, due to altered accessibility of acetyl/methyl group donor and metabolite-modulated enzymatic activity. Finally, we discuss current strategies of metabolic and epigenetic therapy in cardiovascular disease and recommend cell-specific metabolic and gene-targeted site-specific epigenetic alterations for future therapies.

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Ahlenius, Henrik, Soham Chanda, Ashley E. Webb, Issa Yousif, Jesse Karmazin, Stanley B. Prusiner, Anne Brunet, Thomas C. Südhof und Marius Wernig. „FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice“. Proceedings of the National Academy of Sciences 113, Nr. 30 (11.07.2016): 8514–19. http://dx.doi.org/10.1073/pnas.1607079113.

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We and others have shown that embryonic and neonatal fibroblasts can be directly converted into induced neuronal (iN) cells with mature functional properties. Reprogramming of fibroblasts from adult and aged mice, however, has not yet been explored in detail. The ability to generate fully functional iN cells from aged organisms will be particularly important for in vitro modeling of diseases of old age. Here, we demonstrate production of functional iN cells from fibroblasts that were derived from mice close to the end of their lifespan. iN cells from aged mice had apparently normal active and passive neuronal membrane properties and formed abundant synaptic connections. The reprogramming efficiency gradually decreased with fibroblasts derived from embryonic and neonatal mice, but remained similar for fibroblasts from postnatal mice of all ages. Strikingly, overexpression of a transcription factor, forkhead box O3 (FoxO3), which is implicated in aging, blocked iN cell conversion of embryonic fibroblasts, whereas knockout or knockdown of FoxO3 increased the reprogramming efficiency of adult-derived but not of embryonic fibroblasts and also enhanced functional maturation of resulting iN cells. Hence, FoxO3 has a central role in the neuronal reprogramming susceptibility of cells, and the importance of FoxO3 appears to change during development.

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Wei, Zhuang-Yao D., und Ashok K. Shetty. „Treating Parkinson’s disease by astrocyte reprogramming: Progress and challenges“. Science Advances 7, Nr. 26 (Juni 2021): eabg3198. http://dx.doi.org/10.1126/sciadv.abg3198.

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Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder, is typified by both motor and nonmotor symptoms. The current medications provide symptomatic relief but do not stimulate the production of new dopaminergic neurons in the substantia nigra. Astrocyte reprogramming has recently received much attention as an avenue for increasing functional dopaminergic neurons in the mouse PD brain. By targeting a microRNA (miRNA) loop, astrocytes in the mouse brain could be reprogrammed into functional dopaminergic neurons. Such in vivo astrocyte reprogramming in the mouse model of PD has successfully added new dopaminergic neurons to the substantia nigra and increased dopamine levels associated with axonal projections into the striatum. This review deliberates the astrocyte reprogramming methods using specific transcription factors and mRNAs and the progress in generating dopaminergic neurons in vivo. In addition, the translational potential, challenges, and potential risks of astrocyte reprogramming for an enduring alleviation of parkinsonian symptoms are conferred.

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Tang, Yawen, Sajesan Aryal, Xiaoxiao Geng, Xinyue Zhou, Vladimir G. Fast, Jianyi Zhang, Rui Lu und Yang Zhou. „TBX20 Improves Contractility and Mitochondrial Function During Direct Human Cardiac Reprogramming“. Circulation 146, Nr. 20 (15.11.2022): 1518–36. http://dx.doi.org/10.1161/circulationaha.122.059713.

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Background: Direct cardiac reprogramming of fibroblasts into cardiomyocytes has emerged as a promising strategy to remuscularize injured myocardium. However, it is insufficient to generate functional induced cardiomyocytes from human fibroblasts using conventional reprogramming cocktails, and the underlying molecular mechanisms are not well studied. Methods: To discover potential missing factors for human direct reprogramming, we performed transcriptomic comparison between human induced cardiomyocytes and functional cardiomyocytes. Results: We identified TBX20 (T-box transcription factor 20) as the top cardiac gene that is unable to be activated by the MGT133 reprogramming cocktail ( MEF2C , GATA4 , TBX5 , and miR-133 ). TBX20 is required for normal heart development and cardiac function in adult cardiomyocytes, yet its role in cardiac reprogramming remains undefined. We show that the addition of TBX20 to the MGT133 cocktail (MGT+TBX20) promotes cardiac reprogramming and activates genes associated with cardiac contractility, maturation, and ventricular heart. Human induced cardiomyocytes produced with MGT+TBX20 demonstrated more frequent beating, calcium oscillation, and higher energy metabolism as evidenced by increased mitochondria numbers and mitochondrial respiration. Mechanistically, comprehensive transcriptomic, chromatin occupancy, and epigenomic studies revealed that TBX20 colocalizes with MGT reprogramming factors at cardiac gene enhancers associated with heart contraction, promotes chromatin binding and co-occupancy of MGT factors at these loci, and synergizes with MGT for more robust activation of target gene transcription. Conclusions: TBX20 consolidates MGT cardiac reprogramming factors to activate cardiac enhancers to promote cardiac cell fate conversion. Human induced cardiomyocytes generated with TBX20 showed enhanced cardiac function in contractility and mitochondrial respiration.

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Kim, Jaehong. „Regulation of Immune Cell Functions by Metabolic Reprogramming“. Journal of Immunology Research 2018 (2018): 1–12. http://dx.doi.org/10.1155/2018/8605471.

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Recent findings show that the metabolic status of immune cells can determine immune responses. Metabolic reprogramming between aerobic glycolysis and oxidative phosphorylation, previously speculated as exclusively observable in cancer cells, exists in various types of immune and stromal cells in many different pathological conditions other than cancer. The microenvironments of cancer, obese adipose, and wound-repairing tissues share common features of inflammatory reactions. In addition, the metabolic changes in macrophages and T cells are now regarded as crucial for the functional plasticity of the immune cells and responsible for the progression and regression of many pathological processes, notably cancer. It is possible that metabolic changes in the microenvironment induced by other cellular components are responsible for the functional plasticity of immune cells. This review explores the molecular mechanisms responsible for metabolic reprogramming in macrophages and T cells and also provides a summary of recent updates with regard to the functional modulation of the immune cells by metabolic changes in the microenvironment, notably the tumor microenvironment.

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Rogers, J. M., und H. Suga. „Discovering functional, non-proteinogenic amino acid containing, peptides using genetic code reprogramming“. Organic & Biomolecular Chemistry 13, Nr. 36 (2015): 9353–63. http://dx.doi.org/10.1039/c5ob01336d.

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Wang, Aline Yen Ling, und Charles Yuen Yung Loh. „Episomal Induced Pluripotent Stem Cells: Functional and Potential Therapeutic Applications“. Cell Transplantation 28, Nr. 1_suppl (14.11.2019): 112S—131S. http://dx.doi.org/10.1177/0963689719886534.

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The term episomal induced pluripotent stem cells (EiPSCs) refers to somatic cells that are reprogrammed into induced pluripotent stem cells (iPSCs) using non-integrative episomal vector methods. This reprogramming process has a better safety profile compared with integrative methods using viruses. There is a current trend toward using episomal plasmid reprogramming to generate iPSCs because of the improved safety profile. Clinical reports of potential human cell sources that have been successfully reprogrammed into EiPSCs are increasing, but no review or summary has been published. The functional applications of EiPSCs and their potential uses in various conditions have been described, and these may be applicable to clinical scenarios. This review summarizes the current direction of EiPSC research and the properties of these cells with the aim of explaining their potential role in clinical applications and functional restoration.

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Chen, Olivia, und Li Qian. „Direct Cardiac Reprogramming: Advances in Cardiac Regeneration“. BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/580406.

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Heart disease is one of the lead causes of death worldwide. Many forms of heart disease, including myocardial infarction and pressure-loading cardiomyopathies, result in irreversible cardiomyocyte death. Activated fibroblasts respond to cardiac injury by forming scar tissue, but ultimately this response fails to restore cardiac function. Unfortunately, the human heart has little regenerative ability and long-term outcomes following acute coronary events often include chronic and end-stage heart failure. Building upon years of research aimed at restoring functional cardiomyocytes, recent advances have been made in the direct reprogramming of fibroblasts toward a cardiomyocyte cell fate bothin vitroandin vivo. Several experiments show functional improvements in mouse models of myocardial infarction followingin situgeneration of cardiomyocyte-like cells from endogenous fibroblasts. Though many of these studies are in an early stage, this nascent technology holds promise for future applications in regenerative medicine. In this review, we discuss the history, progress, methods, challenges, and future directions of direct cardiac reprogramming.

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Liu, Kuangpin, Wei Ma, Chunyan Li, Junjun Li, Xingkui Zhang, Jie Liu, Wei Liu et al. „Advances in transcription factors related to neuroglial cell reprogramming“. Translational Neuroscience 11, Nr. 1 (20.02.2020): 17–27. http://dx.doi.org/10.1515/tnsci-2020-0004.

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AbstractNeuroglial cells have a high level of plasticity, and many types of these cells are present in the nervous system. Neuroglial cells provide diverse therapeutic targets for neurological diseases and injury repair. Cell reprogramming technology provides an efficient pathway for cell transformation during neural regeneration, while transcription factor-mediated reprogramming can facilitate the understanding of how neuroglial cells mature into functional neurons and promote neurological function recovery.

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Thomson, Alison J., Hadrien Pierart, Stephen Meek, Alexandra Bogerman, Linda Sutherland, Helen Murray, Edward Mountjoy et al. „Reprogramming Pig Fetal Fibroblasts Reveals a Functional LIF Signaling Pathway“. Cellular Reprogramming 14, Nr. 2 (April 2012): 112–22. http://dx.doi.org/10.1089/cell.2011.0078.

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Arnholdt-Schmitt, Birgit, José H. Costa und Dirce Fernandes de Melo. „AOX – a functional marker for efficient cell reprogramming under stress?“ Trends in Plant Science 11, Nr. 6 (Juni 2006): 281–87. http://dx.doi.org/10.1016/j.tplants.2006.05.001.

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Huang, Pengyu, Ludi Zhang, Yimeng Gao, Zhiying He, Dan Yao, Zhitao Wu, Jin Cen et al. „Direct Reprogramming of Human Fibroblasts to Functional and Expandable Hepatocytes“. Cell Stem Cell 14, Nr. 3 (März 2014): 370–84. http://dx.doi.org/10.1016/j.stem.2014.01.003.

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Bar-Nur, Ori, Mattia F. M. Gerli, Bruno Di Stefano, Albert E. Almada, Amy Galvin, Amy Coffey, Aaron J. Huebner et al. „Direct Reprogramming of Mouse Fibroblasts into Functional Skeletal Muscle Progenitors“. Stem Cell Reports 10, Nr. 5 (Mai 2018): 1505–21. http://dx.doi.org/10.1016/j.stemcr.2018.04.009.

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Grealish, Shane, Johan Jakobsson und Malin Parmar. „Lineage reprogramming: A shortcut to generating functional neurons from fibroblasts“. Cell Cycle 10, Nr. 20 (15.10.2011): 3421–22. http://dx.doi.org/10.4161/cc.10.20.17691.

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Teijeira, Alvaro, Sara Labiano, Saray Garasa, Iñaki Etxeberria, Eva Santamaría, Ana Rouzaut, Michel Enamorado et al. „Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation“. Cancer Immunology Research 6, Nr. 7 (20.04.2018): 798–811. http://dx.doi.org/10.1158/2326-6066.cir-17-0767.

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Ieda, Masaki, Ji-Dong Fu, Paul Delgado-Olguin, Vasanth Vedantham, Yohei Hayashi, Benoit G. Bruneau und Deepak Srivastava. „Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors“. Cell 142, Nr. 3 (August 2010): 375–86. http://dx.doi.org/10.1016/j.cell.2010.07.002.

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Moorlag, Simone J. C. F. M., Yessica Alina Rodriguez-Rosales, Joshua Gillard, Stephanie Fanucchi, Kate Theunissen, Boris Novakovic, Cynthia M. de Bont et al. „BCG Vaccination Induces Long-Term Functional Reprogramming of Human Neutrophils“. Cell Reports 33, Nr. 7 (November 2020): 108387. http://dx.doi.org/10.1016/j.celrep.2020.108387.

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Bajpai, Vivek K., Laura Kerosuo, Georgios Tseropoulos, Kirstie A. Cummings, Xiaoyan Wang, Pedro Lei, Biao Liu et al. „Reprogramming Postnatal Human Epidermal Keratinocytes Toward Functional Neural Crest Fates“. STEM CELLS 35, Nr. 5 (05.03.2017): 1402–15. http://dx.doi.org/10.1002/stem.2583.

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Chandravanshi, Bhawna, und Ramesh Bhonde. „Reprogramming mouse embryo fibroblasts to functional islets without genetic manipulation“. Journal of Cellular Physiology 233, Nr. 2 (11.08.2017): 1627–37. http://dx.doi.org/10.1002/jcp.26068.

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Mehdizadeh, Amir, und Masoud Darabi. „Reprogrammed Cell?based Therapy for Liver Disease: From Lab to Clinic“. Journal of Renal and Hepatic Disorders 1, Nr. 1 (03.02.2017): 20–28. http://dx.doi.org/10.15586/jrenhep.2017.6.

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A large number of patients are affected by liver dysfunction worldwide. Liver transplantation is the only efficient treatment in a variety of enduring liver disorders including inherent and end-stage liver diseases. The generation of human functional hepatocytes in high quantities for liver cell therapy is an important goal for ongoing therapies in regenerative medicine. Reprogrammed cells are considered as a promising and unlimited source of hepatocytes, mainly because of their expected lack of immunogenicity and minimized ethical concerns in clinical applications. Despite gained advances in the reprogramming of somatic cells to functional hepatocytes in vitro, production of primary adult hepatocytes that can proliferate in vivo still remains inaccessible. As part of efforts toward translation of cell reprogramming science into clinical practice, more careful cell selection strategies should be integrated into improvement of dedifferentiation and redifferentiation protocols, especially in precision medicine where gene correction is needed. Furthermore, advances in cellular reprogramming highlight the need for developing and evaluating novel standards addressing clinical research interests in this field.

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Kaimakis, Polynikis, Emma de Pater, Christina Eich, Parham Solaimani Kartalaei, Mari-Liis Kauts, Chris S. Vink, Reinier van der Linden et al. „Functional and molecular characterization of mouse Gata2-independent hematopoietic progenitors“. Blood 127, Nr. 11 (17.03.2016): 1426–37. http://dx.doi.org/10.1182/blood-2015-10-673749.

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Key Points A new Gata2 reporter indicates that all HSCs express Gata2 and corroborates findings that Gata2 is not required for generation of all HPCs. Isolatable non–Gata2-expressing HPCs show less potency and a distinct genetic program, thus having implications for reprogramming strategies.

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Wahlestedt, Martin, Gudmundur L. Norddahl, Gerd Sten, Amol Ugale, Mary-Ann Micha Frisk, Ragnar Mattsson, Tomas Deierborg, Mikael Sigvardsson und David Bryder. „An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state“. Blood 121, Nr. 21 (23.05.2013): 4257–64. http://dx.doi.org/10.1182/blood-2012-11-469080.

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Meiliana, Anna, und Andi Wijaya. „Epigenetic Reprogramming Induced Pluripotency“. Indonesian Biomedical Journal 3, Nr. 2 (01.08.2011): 93. http://dx.doi.org/10.18585/inabj.v3i2.139.

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BACKGROUND: The ability to reprogram mature cells to an embryonic-like state by nuclear transfer or by inducing the expression of key transcription factors has provided us with critical opportunities to linearly map the epigenetic parameters that are essential for attaining pluripotency.CONTENT: Epigenetic reprogramming describes a switch in gene expression of one kind of cell to that of another unrelated cell type. Early studies in frog cloning provided some of the first experimental evidence for reprogramming. Subsequent procedures included mammalian somatic cell nuclear transfer, cell fusion, induction of pluripotency by ectopic gene expression, and direct reprogramming. Through these methods it becomes possible to derive one kind of specialized cell (such as a brain cell) from another, more accessible tissue, such as skin in the same individual. This has potential applications for cell replacement without the immunosuppression treatments commonly required when cells are transferred between genetically different individuals.SUMMARY: Reprogramming with transcription factors offers tremendous promise for the future development of patient-specific pluripotent cells and for studies of human disease. The identification of optimized protocols for the differentiation of iPS cells and ES cells into multiple functional cell types in vitro and their proper engraftment in vivo will be challenged in the coming years. Given that the first small molecule approaches aimed at activating pluripotency genes have already been devised and that murine iPS cells have recently been derived by using non-integrative transient expression strategies of the reprogramming factors, we expect that human iPS cells without permanent genetic alterations will soon be generated.KEYWORDS: epigenetics, reprogramming, pluripotency, stem cells, iPS cells, chromatin, DNA methylation

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Bruzelius, Andreas, Srisaiyini Kidnapillai, Janelle Drouin-Ouellet, Tom Stoker, Roger A. Barker und Daniella Rylander Ottosson. „Reprogramming Human Adult Fibroblasts into GABAergic Interneurons“. Cells 10, Nr. 12 (08.12.2021): 3450. http://dx.doi.org/10.3390/cells10123450.

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Direct reprogramming is an appealing strategy to generate neurons from a somatic cell by forced expression of transcription factors. The generated neurons can be used for both cell replacement strategies and disease modelling. Using this technique, previous studies have shown that γ-aminobutyric acid (GABA) expressing interneurons can be generated from different cell sources, such as glia cells or fetal fibroblasts. Nevertheless, the generation of neurons from adult human fibroblasts, an easily accessible cell source to obtain patient-derived neurons, has proved to be challenging due to the intrinsic blockade of neuronal commitment. In this paper, we used an optimized protocol for adult skin fibroblast reprogramming based on RE1 Silencing Transcription Factor (REST) inhibition together with a combination of GABAergic fate determinants to convert human adult skin fibroblasts into GABAergic neurons. Our results show a successful conversion in 25 days with upregulation of neuronal gene and protein expression levels. Moreover, we identified specific gene combinations that converted fibroblasts into neurons of a GABAergic interneuronal fate. Despite the well-known difficulty in converting adult fibroblasts into functional neurons in vitro, we could detect functional maturation in the induced neurons. GABAergic interneurons have relevance for cognitive impairments and brain disorders, such as Alzheimer’s and Parkinson’s diseases, epilepsy, schizophrenia and autism spectrum disorders.

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Testa, Gianluca, Giorgia Di Benedetto und Fabiana Passaro. „Advanced Technologies to Target Cardiac Cell Fate Plasticity for Heart Regeneration“. International Journal of Molecular Sciences 22, Nr. 17 (01.09.2021): 9517. http://dx.doi.org/10.3390/ijms22179517.

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The adult human heart can only adapt to heart diseases by starting a myocardial remodeling process to compensate for the loss of functional cardiomyocytes, which ultimately develop into heart failure. In recent decades, the evolution of new strategies to regenerate the injured myocardium based on cellular reprogramming represents a revolutionary new paradigm for cardiac repair by targeting some key signaling molecules governing cardiac cell fate plasticity. While the indirect reprogramming routes require an in vitro engineered 3D tissue to be transplanted in vivo, the direct cardiac reprogramming would allow the administration of reprogramming factors directly in situ, thus holding great potential as in vivo treatment for clinical applications. In this framework, cellular reprogramming in partnership with nanotechnologies and bioengineering will offer new perspectives in the field of cardiovascular research for disease modeling, drug screening, and tissue engineering applications. In this review, we will summarize the recent progress in developing innovative therapeutic strategies based on manipulating cardiac cell fate plasticity in combination with bioengineering and nanotechnology-based approaches for targeting the failing heart.

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Márquez, Javier, und José M. Matés. „Tumor Metabolome: Therapeutic Opportunities Targeting Cancer Metabolic Reprogramming“. Cancers 13, Nr. 2 (16.01.2021): 314. http://dx.doi.org/10.3390/cancers13020314.

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The study of cancer metabolism is regaining center stage and becoming a hot topic in tumor biology and clinical research, after a period where such kind of experimental approaches were somehow forgotten or disregarded in favor of powerful functional genomic and proteomic studies [...]

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Aguilar, Carlos A. „Reprogramming to help the old see like the young“. Science Translational Medicine 12, Nr. 574 (16.12.2020): eabf7738. http://dx.doi.org/10.1126/scitranslmed.abf7738.

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Xie, H., N. Dubey, W. Shim, C. J. A. Ramachandra, K. S. Min, T. Cao und V. Rosa. „Functional Odontoblastic-Like Cells Derived from Human iPSCs“. Journal of Dental Research 97, Nr. 1 (12.09.2017): 77–83. http://dx.doi.org/10.1177/0022034517730026.

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The induced pluripotent stem cells (iPSCs) have an intrinsic capability for indefinite self-renewal and large-scale expansion and can differentiate into all types of cells. Here, we tested the potential of iPSCs from dental pulp stem cells (DPSCs) to differentiate into functional odontoblasts. DPSCs were reprogrammed into iPSCs via electroporation of reprogramming factors OCT-4, SOX2, KLF4, LIN28, and L-MYC. The iPSCs presented overexpression of the reprogramming genes and high protein expressions of alkaline phosphatase, OCT4, and TRA-1-60 in vitro and generated tissues from 3 germ layers in vivo. Dentin discs with poly-L-lactic acid scaffolds containing iPSCs were implanted subcutaneously into immunodeficient mice. After 28 d from implantation, the iPSCs generated a pulp-like tissue with the presence of tubular dentin in vivo. The differentiation potential after long-term expansion was assessed in vitro. iPSCs and DPSCs of passages 4 and 14 were treated with either odontogenic medium or extract of bioactive cement for 28 d. Regardless of the passage tested, iPSCs expressed putative markers of odontoblastic differentiation and kept the same mineralization potential, while DPSC P14 failed to do the same. Analysis of these data collectively demonstrates that human iPSCs can be a source to derive human odontoblasts for dental pulp research and test bioactivity of materials.

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Swinstead, Erin E., Ville Paakinaho und Gordon L. Hager. „Chromatin reprogramming in breast cancer“. Endocrine-Related Cancer 25, Nr. 7 (Juli 2018): R385—R404. http://dx.doi.org/10.1530/erc-18-0033.

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Reprogramming of the chromatin landscape is a critical component to the transcriptional response in breast cancer. Effects of sex hormones such as estrogens and progesterone have been well described to have a critical impact on breast cancer proliferation. However, the complex network of the chromatin landscape, enhancer regions and mode of function of steroid receptors (SRs) and other transcription factors (TFs), is an intricate web of signaling and functional processes that is still largely misunderstood at the mechanistic level. In this review, we describe what is currently known about the dynamic interplay between TFs with chromatin and the reprogramming of enhancer elements. Emphasis has been placed on characterizing the different modes of action of TFs in regulating enhancer activity, specifically, how different SRs target enhancer regions to reprogram chromatin in breast cancer cells. In addition, we discuss current techniques employed to study enhancer function at a genome-wide level. Further, we have noted recent advances in live cell imaging technology. These single-cell approaches enable the coupling of population-based assays with real-time studies to address many unsolved questions about SRs and chromatin dynamics in breast cancer.

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Hsu, Jasper, Andreea Reilly, Brian J. Hayes, Courtnee A. Clough, Eric Q. Konnick, Beverly Torok-Storb, Suleyman Gulsuner et al. „Reprogramming identifies functionally distinct stages of clonal evolution in myelodysplastic syndromes“. Blood 134, Nr. 2 (11.07.2019): 186–98. http://dx.doi.org/10.1182/blood.2018884338.

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Abstract Myeloid neoplasms, including myelodysplastic syndromes (MDS), are genetically heterogeneous disorders driven by clonal acquisition of somatic mutations in hematopoietic stem and progenitor cells (HPCs). The order of premalignant mutations and their impact on HPC self-renewal and differentiation remain poorly understood. We show that episomal reprogramming of MDS patient samples generates induced pluripotent stem cells from single premalignant cells with a partial complement of mutations, directly informing the temporal order of mutations in the individual patient. Reprogramming preferentially captured early subclones with fewer mutations, which were rare among single patient cells. To evaluate the functional impact of clonal evolution in individual patients, we differentiated isogenic MDS induced pluripotent stem cells harboring up to 4 successive clonal abnormalities recapitulating a progressive decrease in hematopoietic differentiation potential. SF3B1, in concert with epigenetic mutations, perturbed mitochondrial function leading to accumulation of damaged mitochondria during disease progression, resulting in apoptosis and ineffective erythropoiesis. Reprogramming also informed the order of premalignant mutations in patients with complex karyotype and identified 5q deletion as an early cytogenetic anomaly. The loss of chromosome 5q cooperated with TP53 mutations to perturb genome stability, promoting acquisition of structural and karyotypic abnormalities. Reprogramming thus enables molecular and functional interrogation of preleukemic clonal evolution, identifying mitochondrial function and chromosome stability as key pathways affected by acquisition of somatic mutations in MDS.

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Perveen, Sadia, Roberto Vanni, Marco Lo Iacono, Raffaella Rastaldo und Claudia Giachino. „Direct Reprogramming of Resident Non-Myocyte Cells and Its Potential for In Vivo Cardiac Regeneration“. Cells 12, Nr. 8 (15.04.2023): 1166. http://dx.doi.org/10.3390/cells12081166.

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Cardiac diseases are the foremost cause of morbidity and mortality worldwide. The heart has limited regenerative potential; therefore, lost cardiac tissue cannot be replenished after cardiac injury. Conventional therapies are unable to restore functional cardiac tissue. In recent decades, much attention has been paid to regenerative medicine to overcome this issue. Direct reprogramming is a promising therapeutic approach in regenerative cardiac medicine that has the potential to provide in situ cardiac regeneration. It consists of direct cell fate conversion of one cell type into another, avoiding transition through an intermediary pluripotent state. In injured cardiac tissue, this strategy directs transdifferentiation of resident non-myocyte cells (NMCs) into mature functional cardiac cells that help to restore the native tissue. Over the years, developments in reprogramming methods have suggested that regulation of several intrinsic factors in NMCs can help to achieve in situ direct cardiac reprogramming. Among NMCs, endogenous cardiac fibroblasts have been studied for their potential to be directly reprogrammed into both induced cardiomyocytes and induced cardiac progenitor cells, while pericytes can transdifferentiate towards endothelial cells and smooth muscle cells. This strategy has been indicated to improve heart function and reduce fibrosis after cardiac injury in preclinical models. This review summarizes the recent updates and progress in direct cardiac reprogramming of resident NMCs for in situ cardiac regeneration.

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Wang, Aline Yen Ling. „Application of Modified mRNA in Somatic Reprogramming to Pluripotency and Directed Conversion of Cell Fate“. International Journal of Molecular Sciences 22, Nr. 15 (29.07.2021): 8148. http://dx.doi.org/10.3390/ijms22158148.

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Modified mRNA (modRNA)-based somatic reprogramming is an effective and safe approach that overcomes the genomic mutation risk caused by viral integrative methods. It has improved the disadvantages of conventional mRNA and has better stability and immunogenicity. The modRNA molecules encoding multiple pluripotent factors have been applied successfully in reprogramming somatic cells such as fibroblasts, mesenchymal stem cells, and amniotic fluid stem cells to generate pluripotent stem cells (iPSCs). Moreover, it also can be directly used in the terminal differentiation of stem cells and fibroblasts into functional therapeutic cells, which exhibit great promise in disease modeling, drug screening, cell transplantation therapy, and regenerative medicine. In this review, we summarized the reprogramming applications of modified mRNA in iPSC generation and therapeutic applications of functionally differentiated cells.

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Long, Jincheng, James Walker, Wenjing She, Billy Aldridge, Hongbo Gao, Samuel Deans, Martin Vickers und Xiaoqi Feng. „Nurse cell–derived small RNAs define paternal epigenetic inheritance in Arabidopsis“. Science 373, Nr. 6550 (01.07.2021): eabh0556. http://dx.doi.org/10.1126/science.abh0556.

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The plant male germline undergoes DNA methylation reprogramming, which methylates genes de novo and thereby alters gene expression and regulates meiosis. Here, we reveal the molecular mechanism underlying this reprogramming. We demonstrate that genic methylation in the male germline, from meiocytes to sperm, is established by 24-nucleotide small interfering RNAs (siRNAs) transcribed from transposons with imperfect sequence homology. These siRNAs are synthesized by meiocyte nurse cells (tapetum) through activity of CLSY3, a chromatin remodeler absent in other anther cells. Tapetal siRNAs govern germline methylation throughout the genome, including the inherited methylation patterns in sperm. Tapetum-derived siRNAs also silence germline transposons, safeguarding genome integrity. Our results reveal that tapetal siRNAs are sufficient to reconstitute germline methylation patterns and drive functional methylation reprogramming throughout the male germline.

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Hou, Pingping, Yanqin Li, Xu Zhang, Chun Liu, Jingyang Guan, Honggang Li, Ting Zhao et al. „Pluripotent Stem Cells Induced from Mouse Somatic Cells by Small-Molecule Compounds“. Science 341, Nr. 6146 (18.07.2013): 651–54. http://dx.doi.org/10.1126/science.1239278.

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Pluripotent stem cells can be induced from somatic cells, providing an unlimited cell resource, with potential for studying disease and use in regenerative medicine. However, genetic manipulation and technically challenging strategies such as nuclear transfer used in reprogramming limit their clinical applications. Here, we show that pluripotent stem cells can be generated from mouse somatic cells at a frequency up to 0.2% using a combination of seven small-molecule compounds. The chemically induced pluripotent stem cells resemble embryonic stem cells in terms of their gene expression profiles, epigenetic status, and potential for differentiation and germline transmission. By using small molecules, exogenous “master genes” are dispensable for cell fate reprogramming. This chemical reprogramming strategy has potential use in generating functional desirable cell types for clinical applications.

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Stout, Robert D., Stephanie K. Watkins und Jill Suttles. „Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages“. Journal of Leukocyte Biology 86, Nr. 5 (15.07.2009): 1105–9. http://dx.doi.org/10.1189/jlb.0209073.

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Cardon, Tristan, Julien Franck, Etienne Coyaud, Estelle M. N. Laurent, Marina Damato, Michele Maffia, Daniele Vergara, Isabelle Fournier und Michel Salzet. „Alternative proteins are functional regulators in cell reprogramming by PKA activation“. Nucleic Acids Research 48, Nr. 14 (23.04.2020): 7864–82. http://dx.doi.org/10.1093/nar/gkaa277.

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Abstract It has been recently shown that many proteins are lacking from reference databases used in mass spectrometry analysis, due to their translation templated on alternative open reading frames. This questions our current understanding of gene annotation and drastically expands the theoretical proteome complexity. The functions of these alternative proteins (AltProts) still remain largely unknown. We have developed a large-scale and unsupervised approach based on cross-linking mass spectrometry (XL-MS) followed by shotgun proteomics to gather information on the functional role of AltProts by mapping them back into known signalling pathways through the identification of their reference protein (RefProt) interactors. We have identified and profiled AltProts in a cancer cell reprogramming system: NCH82 human glioma cells after 0, 16, 24 and 48 h Forskolin stimulation. Forskolin is a protein kinase A activator inducing cell differentiation and epithelial–mesenchymal transition. Our data show that AltMAP2, AltTRNAU1AP and AltEPHA5 interactions with tropomyosin 4 are downregulated under Forskolin treatment. In a wider perspective, Gene Ontology and pathway enrichment analysis (STRING) revealed that RefProts associated with AltProts are enriched in cellular mobility and transfer RNA regulation. This study strongly suggests novel roles of AltProts in multiple essential cellular functions and supports the importance of considering them in future biological studies.

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Weinberg, Marc S., Hugh E. Criswell, Sara K. Powell, Aadra P. Bhatt und Thomas J. McCown. „Viral Vector Reprogramming of Adult Resident Striatal Oligodendrocytes into Functional Neurons“. Molecular Therapy 25, Nr. 4 (April 2017): 928–34. http://dx.doi.org/10.1016/j.ymthe.2017.01.016.

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Li, Xiang, Xiaohan Zuo, Junzhan Jing, Yantao Ma, Jiaming Wang, Defang Liu, Jialiang Zhu et al. „Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons“. Cell Stem Cell 17, Nr. 2 (August 2015): 195–203. http://dx.doi.org/10.1016/j.stem.2015.06.003.

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Charbonnier, Louis-Marie, Ye Cui, Emmanuel Stephen-Victor, Hani Harb, David Lopez, Jack J. Bleesing, Maria I. Garcia-Lloret et al. „Functional reprogramming of regulatory T cells in the absence of Foxp3“. Nature Immunology 20, Nr. 9 (05.08.2019): 1208–19. http://dx.doi.org/10.1038/s41590-019-0442-x.

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