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Pancreatic Inflammation Redirects Acinar to β Cell Reprogramming.
Clayton HW, Osipovich AB, Stancill JS, Schneider JD, Vianna PG, Shanks CM, Yuan W, Gu G, Manduchi E, Stoeckert CJ, Magnuson MA
(2016) Cell Rep 17: 2028-2041
MeSH Terms: Acinar Cells, Adenoviridae, Alleles, Animals, Cellular Reprogramming, Diabetes Mellitus, Experimental, Doxycycline, Gene Expression Profiling, Homeodomain Proteins, Immunity, Inflammation, Insulin-Secreting Cells, Macrophages, Metaplasia, Mice, Transgenic, Organ Size, Pancreas, Pancreatic Ducts, Reproducibility of Results, Transcription Factors, Transgenes
Show Abstract · Added November 18, 2016
Using a transgenic mouse model to express MafA, Pdx1, and Neurog3 (3TF) in a pancreatic acinar cell- and doxycycline-dependent manner, we discovered that the outcome of transcription factor-mediated acinar to β-like cellular reprogramming is dependent on both the magnitude of 3TF expression and on reprogramming-induced inflammation. Overly robust 3TF expression causes acinar cell necrosis, resulting in marked inflammation and acinar-to-ductal metaplasia. Generation of new β-like cells requires limiting reprogramming-induced inflammation, either by reducing 3TF expression or by eliminating macrophages. The new β-like cells were able to reverse streptozotocin-induced diabetes 6 days after inducing 3TF expression but failed to sustain their function after removal of the reprogramming factors.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
3 Communities
2 Members
2 Resources
21 MeSH Terms
Fluorescence-based measurement of cystine uptake through xCT shows requirement for ROS detoxification in activated lymphocytes.
Siska PJ, Kim B, Ji X, Hoeksema MD, Massion PP, Beckermann KE, Wu J, Chi JT, Hong J, Rathmell JC
(2016) J Immunol Methods 438: 51-58
MeSH Terms: Amino Acid Transport System y+, B-Lymphocytes, Cell Line, Tumor, Cellular Reprogramming, Cystine, Flow Cytometry, Fluorescein-5-isothiocyanate, Fluorescence, Fluorescent Dyes, Glutathione, Humans, Lymphocyte Activation, Microscopy, Fluorescence, Reactive Oxygen Species, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Up-Regulation
Show Abstract · Added January 29, 2018
T and B lymphocytes undergo metabolic re-programming upon activation that is essential to allow bioenergetics, cell survival, and intermediates for cell proliferation and function. To support changes in the activity of signaling pathways and to provide sufficient and necessary intracellular metabolites, uptake of extracellular nutrients increases sharply with metabolic re-programming. One result of increased metabolic activity can be reactive oxygen species (ROS), which can be toxic when accumulated in excess. Uptake of cystine allows accumulation of cysteine that is necessary for glutathione synthesis and ROS detoxification. Cystine uptake is required for T cell activation and function but measurements based on radioactive labeling do not allow analysis on single cell level. Here we show the critical role for cystine uptake in T cells using a method for measurement of cystine uptake using a novel CystineFITC probe. T cell receptor stimulation lead to upregulation of the cystine transporter xCT (SLC7a11) and increased cystine uptake in CD4+ and CD8+ human T cells. Similarly, lipopolysaccharide stimulation increased cystine uptake in human B cells. The CystineFITC probe was not toxic and could be metabolized to prevent cystine starvation induced cell death. Furthermore, blockade of xCT or competition with natural cystine decreased uptake of CystineFITC. CystineFITC is thus a versatile tool that allows measurement of cystine uptake on single cell level and shows the critical role for cystine uptake for T cell ROS regulation and activation.
Copyright © 2016 Elsevier B.V. All rights reserved.
0 Communities
1 Members
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18 MeSH Terms
Two waves of de novo methylation during mouse germ cell development.
Molaro A, Falciatori I, Hodges E, Aravin AA, Marran K, Rafii S, McCombie WR, Smith AD, Hannon GJ
(2014) Genes Dev 28: 1544-9
MeSH Terms: Animals, Cellular Reprogramming, DNA Methylation, Epigenesis, Genetic, Male, Mice, RNA, Small Interfering, Retroelements, Spermatocytes, Spermatogenesis, Transcription, Genetic
Show Abstract · Added February 15, 2016
During development, mammalian germ cells reprogram their epigenomes via a genome-wide erasure and de novo rewriting of DNA methylation marks. We know little of how methylation patterns are specifically determined. The piRNA pathway is thought to target the bulk of retrotransposon methylation. Here we show that most retrotransposon sequences are modified by default de novo methylation. However, potentially active retrotransposon copies evade this initial wave, likely mimicking features of protein-coding genes. These elements remain transcriptionally active and become targets of piRNA-mediated methylation. Thus, we posit that these two waves play essential roles in resetting germ cell epigenomes at each generation.
© 2014 Molaro et al.; Published by Cold Spring Harbor Laboratory Press.
0 Communities
1 Members
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11 MeSH Terms
Characterization of vector-based delivery of neurogenin-3 in murine diabetes.
Phillips N, Kay MA
(2014) Hum Gene Ther 25: 651-61
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cellular Reprogramming, Diabetes Mellitus, Experimental, Genetic Therapy, Genetic Vectors, Hyperglycemia, Insulin-Secreting Cells, Mice, Nerve Tissue Proteins
Show Abstract · Added October 19, 2016
Treatment of type 1 diabetes with gene transfer-induced cellular reprogramming requires a pancreatic transcription factor such as Neurogenin-3 (Ngn3) and as of yet unknown component of the adenoviral particle. Despite intensive study, there are many unsolved processes related to the mechanisms and physiological parameters related to diabetes correction using this approach. While we confirm that systemic delivery of adenovirus (Ad)-Ngn3 provides long-lasting correction of streptozotocin (STZ)-induced hyperglycemia and restoration of growth curves, we found that insulin levels and glucose tolerance tests are not fully restored. By altering the innate and antigen-specific immune responses, we establish that the former likely plays some role in the reprogramming process. Interestingly, Ad-hNgn3 therapy in diabetic animals appeared to protect them from secondary STZ challenge. The resistance to secondary STZ response was more pronounced at later time points, indicating that a period of cell maturation and/or expansion may be required in order to promote lasting correction. More importantly, these results suggest that the long-term reprogrammed cells are not fully reprogrammed into β-cells, which in the case of autoimmune diabetes may be advantageous in a long-term treatment strategy. Finally, we show that the prophylactic administration of Ad-hNgn3 before diabetic induction protected mice from developing hyperglycemia, demonstrating the potential for reducing or eliminating disease progression should treatment be initiated early or before onset of symptoms.
0 Communities
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10 MeSH Terms
Deterministic direct reprogramming of somatic cells to pluripotency.
Rais Y, Zviran A, Geula S, Gafni O, Chomsky E, Viukov S, Mansour AA, Caspi I, Krupalnik V, Zerbib M, Maza I, Mor N, Baran D, Weinberger L, Jaitin DA, Lara-Astiaso D, Blecher-Gonen R, Shipony Z, Mukamel Z, Hagai T, Gilad S, Amann-Zalcenstein D, Tanay A, Amit I, Novershtern N, Hanna JH
(2013) Nature 502: 65-70
MeSH Terms: Animals, Cell Line, Cells, Cultured, Cellular Reprogramming, DNA-Binding Proteins, Embryonic Stem Cells, Female, Gene Expression Regulation, HEK293 Cells, Humans, Induced Pluripotent Stem Cells, Male, Mice, Models, Biological, Transcription Factors
Show Abstract · Added September 15, 2017
Somatic cells can be inefficiently and stochastically reprogrammed into induced pluripotent stem (iPS) cells by exogenous expression of Oct4 (also called Pou5f1), Sox2, Klf4 and Myc (hereafter referred to as OSKM). The nature of the predominant rate-limiting barrier(s) preventing the majority of cells to successfully and synchronously reprogram remains to be defined. Here we show that depleting Mbd3, a core member of the Mbd3/NuRD (nucleosome remodelling and deacetylation) repressor complex, together with OSKM transduction and reprogramming in naive pluripotency promoting conditions, result in deterministic and synchronized iPS cell reprogramming (near 100% efficiency within seven days from mouse and human cells). Our findings uncover a dichotomous molecular function for the reprogramming factors, serving to reactivate endogenous pluripotency networks while simultaneously directly recruiting the Mbd3/NuRD repressor complex that potently restrains the reactivation of OSKM downstream target genes. Subsequently, the latter interactions, which are largely depleted during early pre-implantation development in vivo, lead to a stochastic and protracted reprogramming trajectory towards pluripotency in vitro. The deterministic reprogramming approach devised here offers a novel platform for the dissection of molecular dynamics leading to establishing pluripotency at unprecedented flexibility and resolution.
0 Communities
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1 Resources
15 MeSH Terms
The plastic pancreas.
Ziv O, Glaser B, Dor Y
(2013) Dev Cell 26: 3-7
MeSH Terms: Acinar Cells, Carcinoma, Pancreatic Ductal, Cell Death, Cell Dedifferentiation, Cell Differentiation, Cellular Reprogramming, Endocrine Cells, Humans, Pancreas, Pancreatitis, Regeneration, Stem Cells
Show Abstract · Added August 14, 2013
Pancreas homeostasis is based on replication of differentiated cells in order to maintain proper organ size and function under changing physiological demand. Recent studies suggest that acinar cells, the most abundant cell type in the pancreas, are facultative progenitors capable of reverting to embryonic-like multipotent progenitor cells under injury conditions associated with inflammation. In parallel, it is becoming apparent that within the endocrine pancreas, hormone-producing cells can lose or switch their identity under metabolic stress or in response to single gene mutations. This new view of pancreas dynamics suggests interesting links between pancreas regeneration and pathologies including diabetes and pancreatic cancer.
Copyright © 2013 Elsevier Inc. All rights reserved.
0 Communities
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1 Resources
12 MeSH Terms
Adult duct-lining cells can reprogram into β-like cells able to counter repeated cycles of toxin-induced diabetes.
Al-Hasani K, Pfeifer A, Courtney M, Ben-Othman N, Gjernes E, Vieira A, Druelle N, Avolio F, Ravassard P, Leuckx G, Lacas-Gervais S, Ambrosetti D, Benizri E, Hecksher-Sorensen J, Gounon P, Ferrer J, Gradwohl G, Heimberg H, Mansouri A, Collombat P
(2013) Dev Cell 26: 86-100
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Blood Glucose, Cell Differentiation, Cell Lineage, Cell Movement, Cellular Reprogramming, Diabetes Mellitus, Experimental, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Glucagon-Secreting Cells, Homeodomain Proteins, Hypertrophy, Insulin-Secreting Cells, Mice, Nerve Tissue Proteins, Paired Box Transcription Factors, Pancreatic Ducts, Streptozocin
Show Abstract · Added August 14, 2013
It was recently demonstrated that embryonic glucagon-producing cells in the pancreas can regenerate and convert into insulin-producing β-like cells through the constitutive/ectopic expression of the Pax4 gene. However, whether α cells in adult mice display the same plasticity is unknown. Similarly, the mechanisms underlying such reprogramming remain unclear. We now demonstrate that the misexpression of Pax4 in glucagon(+) cells age-independently induces their conversion into β-like cells and their glucagon shortage-mediated replacement, resulting in islet hypertrophy and in an unexpected islet neogenesis. Combining several lineage-tracing approaches, we show that, upon Pax4-mediated α-to-β-like cell conversion, pancreatic duct-lining precursor cells are continuously mobilized, re-express the developmental gene Ngn3, and successively adopt a glucagon(+) and a β-like cell identity through a mechanism involving the reawakening of the epithelial-to-mesenchymal transition. Importantly, these processes can repeatedly regenerate the whole β cell mass and thereby reverse several rounds of toxin-induced diabetes, providing perspectives to design therapeutic regenerative strategies.
Copyright © 2013 Elsevier Inc. All rights reserved.
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1 Resources
19 MeSH Terms
ASCL1 reprograms mouse Muller glia into neurogenic retinal progenitors.
Pollak J, Wilken MS, Ueki Y, Cox KE, Sullivan JM, Taylor RJ, Levine EM, Reh TA
(2013) Development 140: 2619-31
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Biomarkers, Cell Proliferation, Cells, Cultured, Cellular Reprogramming, Chromatin Assembly and Disassembly, Cloning, Molecular, Epidermal Growth Factor, Gene Expression Regulation, HEK293 Cells, Histones, Humans, In Vitro Techniques, Lentivirus, Luminescent Proteins, Mice, Mice, Inbred C57BL, Neurogenesis, Neuroglia, Patch-Clamp Techniques, Regeneration, Retina, Retinal Neurons
Show Abstract · Added November 2, 2015
Non-mammalian vertebrates have a robust ability to regenerate injured retinal neurons from Müller glia (MG) that activate the gene encoding the proneural factor Achaete-scute homolog 1 (Ascl1; also known as Mash1 in mammals) and de-differentiate into progenitor cells. By contrast, mammalian MG have a limited regenerative response and fail to upregulate Ascl1 after injury. To test whether ASCL1 could restore neurogenic potential to mammalian MG, we overexpressed ASCL1 in dissociated mouse MG cultures and intact retinal explants. ASCL1-infected MG upregulated retinal progenitor-specific genes and downregulated glial genes. Furthermore, ASCL1 remodeled the chromatin at its targets from a repressive to an active configuration. MG-derived progenitors differentiated into cells that exhibited neuronal morphologies, expressed retinal subtype-specific neuronal markers and displayed neuron-like physiological responses. These results indicate that a single transcription factor, ASCL1, can induce a neurogenic state in mature MG.
0 Communities
1 Members
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24 MeSH Terms
A novel model of urinary tract differentiation, tissue regeneration, and disease: reprogramming human prostate and bladder cells into induced pluripotent stem cells.
Moad M, Pal D, Hepburn AC, Williamson SC, Wilson L, Lako M, Armstrong L, Hayward SW, Franco OE, Cates JM, Fordham SE, Przyborski S, Carr-Wilkinson J, Robson CN, Heer R
(2013) Eur Urol 64: 753-61
MeSH Terms: Aged, Biomarkers, Cell Differentiation, Cell Lineage, Cell Separation, Cells, Cultured, Cellular Reprogramming, Female, Gene Expression Regulation, Developmental, Humans, Induced Pluripotent Stem Cells, Kallikreins, Kruppel-Like Transcription Factors, Male, Middle Aged, Octamer Transcription Factor-3, Prostate, Prostate-Specific Antigen, Proto-Oncogene Proteins c-myc, Receptors, Androgen, Regeneration, SOXB1 Transcription Factors, Time Factors, Tissue Engineering, Transfection, Ureter, Urinary Bladder, Uroplakins
Show Abstract · Added March 7, 2014
BACKGROUND - Primary culture and animal and cell-line models of prostate and bladder development have limitations in describing human biology, and novel strategies that describe the full spectrum of differentiation from foetal through to ageing tissue are required. Recent advances in biology demonstrate that direct reprogramming of somatic cells into pluripotent embryonic stem cell (ESC)-like cells is possible. These cells, termed induced pluripotent stem cells (iPSCs), could theoretically generate adult prostate and bladder tissue, providing an alternative strategy to study differentiation.
OBJECTIVE - To generate human iPSCs derived from normal, ageing, human prostate (Pro-iPSC), and urinary tract (UT-iPSC) tissue and to assess their capacity for lineage-directed differentiation.
DESIGN, SETTING, AND PARTICIPANTS - Prostate and urinary tract stroma were transduced with POU class 5 homeobox 1 (POU5F1; formerly OCT4), SRY (sex determining region Y)-box 2 (SOX2), Kruppel-like factor 4 (gut) (KLF4), and v-myc myelocytomatosis viral oncogene homolog (avian) (MYC, formerly C-MYC) genes to generate iPSCs.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS - The potential for differentiation into prostate and bladder lineages was compared with classical skin-derived iPSCs. The student t test was used.
RESULTS AND LIMITATIONS - Successful reprogramming of prostate tissue into Pro-iPSCs and bladder and ureter into UT-iPSCs was demonstrated by characteristic ESC morphology, marker expression, and functional pluripotency in generating all three germ-layer lineages. In contrast to conventional skin-derived iPSCs, Pro-iPSCs showed a vastly increased ability to generate prostate epithelial-specific differentiation, as characterised by androgen receptor and prostate-specific antigen induction. Similarly, UT-iPSCs were shown to be more efficient than skin-derived iPSCs in undergoing bladder differentiation as demonstrated by expression of urothelial-specific markers: uroplakins, claudins, and cytokeratin; and stromal smooth muscle markers: α-smooth-muscle actin, calponin, and desmin. These disparities are likely to represent epigenetic differences between individual iPSC lines and highlight the importance of organ-specific iPSCs for tissue-specific studies.
CONCLUSIONS - IPSCs provide an exciting new model to characterise mechanisms regulating prostate and bladder differentiation and to develop novel approaches to disease modelling. Regeneration of bladder cells also provides an exceptional opportunity for translational tissue engineering.
Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
0 Communities
2 Members
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28 MeSH Terms
Heart repair by cardiac reprogramming.
Nam YJ, Song K, Olson EN
(2013) Nat Med 19: 413-5
MeSH Terms: Cellular Reprogramming, Heart, Humans, Myocardial Infarction, Myocytes, Cardiac, Regeneration, Stem Cell Transplantation
Added August 1, 2014
0 Communities
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7 MeSH Terms