Browsing by Subject "Induced Pluripotent Stem Cells"

Now showing 1 - 4 of 4
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    Distinct Neurodegenerative Changes in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia Linked to Mutant TAU Protein
    (Elsevier, 2015-07-14) Ehrlich, Marc; Hallmann, Anna-Lena; Reinhardt, Peter; Araúzo-Bravo, Marcos J.; Korr, Sabrina; Röpke, Albrecht; Psathaki, Olympia E.; Ehling, Petra; Meuth, Sven G.; Oblak, Adrian L.; Murrell, Jill R.; Ghetti, Bernardino; Zaehres, Holm; Schöler, Hans R.; Sterneckert, Jared; Kuhlmann, Tanja; Hargus, Gunnar; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Frontotemporal dementia (FTD) is a frequent form of early-onset dementia and can be caused by mutations in MAPT encoding the microtubule-associated protein TAU. Because of limited availability of neural cells from patients' brains, the underlying mechanisms of neurodegeneration in FTD are poorly understood. Here, we derived induced pluripotent stem cells (iPSCs) from individuals with FTD-associated MAPT mutations and differentiated them into mature neurons. Patient iPSC-derived neurons demonstrated pronounced TAU pathology with increased fragmentation and phospho-TAU immunoreactivity, decreased neurite extension, and increased but reversible oxidative stress response to inhibition of mitochondrial respiration. Furthermore, FTD neurons showed an activation of the unfolded protein response, and a transcriptome analysis demonstrated distinct, disease-associated gene expression profiles. These findings indicate distinct neurodegenerative changes in FTD caused by mutant TAU and highlight the unique opportunity to use neurons differentiated from patient-specific iPSCs to identify potential targets for drug screening purposes and therapeutic intervention.
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    Generation of three dimensional retinal tissue with functional photoreceptors from human iPSCs
    (Nature Publishing Group, 2014-06-10) Zhong, Xiufeng; Gutierrez, Christian; Xue, Tian; Hampton, Christopher; Vergara, M. Natalia; Cao, Li-Hui; Peters, Ann; Park, Tea-Soon; Zambidis, Elias T.; Meyer, Jason S.; Gamm, David M.; Yau, King-Wai; Canto-Soler, M. Valeria; Department of Medical & Molecular Genetics, IU School of Medicine
    Many forms of blindness result from the dysfunction or loss of retinal photoreceptors. Induced pluripotent stem cells (iPSC) hold great potential for the modeling of these diseases or as potential therapeutic agents. However, to fulfill this promise, a remaining challenge is to induce human iPSC to recreate in vitro key structural and functional features of the native retina, in particular the presence of photoreceptors with outer-segment discs and light-sensitivity. Here we report that hiPSC can, in a highly autonomous manner, recapitulate spatiotemporally each of the main steps of retinal development observed in vivo and form 3-dimensional retinal cups that contain all major retinal cell types arranged in their proper layers. Moreover, the photoreceptors in our hiPSC-derived retinal tissue achieve advanced maturation, showing the beginning of outer-segment-disc formation and photosensitivity. This success brings us one step closer to the anticipated use of hiPSC for disease modeling and open possibilities for future therapies.
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    Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types
    (American Society of Hematology, 2013-07-11) Ou, Xuan; O'Leary, Heather A.; Broxmeyer, Hal E.; Microbiology & Immunology, IU School of Medicine
    Dipeptidylpeptidase (DPP) 4 has the potential to truncate proteins with a penultimate alanine, proline, or other selective amino acids at the N-terminus. DPP4 truncation of certain chemokines, colony-stimulating factors, and interleukins have recently been linked to regulation of hematopoietic stem/progenitor cells, more mature blood cells, and other cell types. We believe that the potential role of DPP4 in modification of many regulatory proteins, and their subsequent effects on numerous stem/progenitor and other cell-type functions has not been adequately appreciated. This review addresses the potential implications of the modifying effects of DPP4 on a large number of cytokines and other growth-regulating factors with either proven or putative DPP4 truncation sites on hematopoietic cells, and subsequent effects of DPP4-truncated proteins on multiple aspects of steady-state and stressed hematopoiesis, including stem/progenitor cell, and more mature cell, function.
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    MiR-31/SDHA Axis Regulates Reprogramming Efficiency through Mitochondrial Metabolism
    (Elsevier, 2016-07-12) Lee, Man Ryul; Mantel, Charlie; Lee, Sang A.; Moon, Sung-Hwan; Broxmeyer, Hal E.; Department of Microbiology and Immunology, IU School of Medicine
    Metabolism is remodeled when somatic cells are reprogrammed into induced pluripotent stem cells (iPSCs), but the majority of iPSCs are not fully reprogrammed. In a shift essential for reprogramming, iPSCs use less mitochondrial respiration but increased anaerobic glycolysis for bioenergetics. We found that microRNA 31 (miR-31) suppressed succinate dehydrogenase complex subunit A (SDHA) expression, vital for mitochondrial electron transport chain (ETC) complex II. MiR-31 overexpression in partially reprogrammed iPSCs lowered SDHA expression levels and oxygen consumption rates to that of fully reprogrammed iPSCs, but did not increase the proportion of fully reprogrammed TRA1-60(+) cells in colonies unless miR-31 was co-transduced with Yamanaka factors, which resulted in a 2.7-fold increase in full reprogramming. Thus switching from mitochondrial respiration to glycolytic metabolism through regulation of the miR-31/SDHA axis is critical for lowering the reprogramming threshold. This is supportive of multi-stage reprogramming whereby metabolic remodeling is fundamental.