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neuron direct reprogramming

Qingxi Zhang, Wanling Chen, Sheng Tan, Tongxiang Lin
Parkinson's disease (PD) is the second most frequent neurodegenerative disease after Alzheimer's disease, which is characterized by low level of dopamine expressing in the striatum and deteriorated dopaminergic neurons (DAn) in Substantia nigra pars compacta (SNpc). Generation of PD-derived DAn including differentiation of human embryonic stem cell (hESC), human neural stem cell (hNSC), human induced pluripotent stem cell (hiPSC) and directly reprogramming provide an ideal tool to model PD, which created the possibilities of mimicking key essential pathological processes charactering single cell changes in vitro...
October 20, 2016: Human Gene Therapy
Koki Fujimori, Toshiki Tezuka, Hiroyuki Ishiura, Jun Mitsui, Koichiro Doi, Jun Yoshimura, Hirobumi Tada, Takuya Matsumoto, Miho Isoda, Ryota Hashimoto, Nubutaka Hattori, Takuya Takahashi, Shinichi Morishita, Shoji Tsuji, Wado Akamatsu, Hideyuki Okano
Patient-specific induced pluripotent stem cells (iPSCs) facilitate understanding of the etiology of diseases, discovery of new drugs and development of novel therapeutic interventions. A frequently used starting source of cells for generating iPSCs has been dermal fibroblasts (DFs) isolated from skin biopsies. However, there are also numerous repositories containing lymphoblastoid B-cell lines (LCLs) generated from a variety of patients. To date, this rich bioresource of LCLs has been underused for generating iPSCs, and its use would greatly expand the range of targeted diseases that could be studied by using patient-specific iPSCs...
October 3, 2016: Molecular Brain
Laura Ferraiuolo, Kathrin Meyer, Thomas W Sherwood, Jonathan Vick, Shibi Likhite, Ashley Frakes, Carlos J Miranda, Lyndsey Braun, Paul R Heath, Ricardo Pineda, Christine E Beattie, Pamela J Shaw, Candice C Askwith, Dana McTigue, Brian K Kaspar
Oligodendrocytes have recently been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS). Here we show that, in vitro, mutant superoxide dismutase 1 (SOD1) mouse oligodendrocytes induce WT motor neuron (MN) hyperexcitability and death. Moreover, we efficiently derived human oligodendrocytes from a large number of controls and patients with sporadic and familial ALS, using two different reprogramming methods. All ALS oligodendrocyte lines induced MN death through conditioned medium (CM) and in coculture...
September 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
Hao Yang, Lingling Zhang, Jing An, Qian Zhang, Cuicui Liu, Baorong He, Ding-Jun Hao
Cellular reprogramming is a promising strategy to generate neural stem cells (NSCs) or desired subtype-specific neurons for cell-based therapeutic intervention. By far, the intricate cell event like reprogramming of non-neural cells to desired cell types can be achieved by forced expression of lineage-related transcription factors (TFs), nuclear transfer, a defined set of factors, and via non-coding microRNAs (miRNAs), as well as other precisely defined conditions. In addition, scientists have been trying to develop better approaches for reprogramming, either by using distinct combinations of a set of small molecules and certain TFs or delivery of appropriate small molecules and miRNAs...
September 22, 2016: Molecular Neurobiology
Mou Gao, Qin Dong, Hui Yao, Yan Zhang, Yang Yang, Yuanyuan Dang, Hongtian Zhang, Zhijun Yang, Minhui Xu, Ruxiang Xu
We previously reported that induced neural stem cells (iNSCs) directly reprogrammed from mouse embryonic fibroblasts can expand and differentiate into neurons, astrocytes and oligodendrocytes. Whether iNSCs have immunoregulatory properties in addition to facilitating cell replacement remains uncertain. In this study, we aimed to characterize the immunomodulatory effects of iNSCs on the activation states of microglia and to elucidate the mechanisms underlying these effects. Using a mouse model of closed head injury (CHI), we observed that iNSC grafts decreased the levels of ED1(+)/Iba1(+) and TNF-α(+)/Iba1(+) microglia but increased the levels of IGF1(+)/Iba1(+) microglia in the injured cortex...
September 17, 2016: Brain, Behavior, and Immunity
Qunzhou Zhang, Phuong Nguyen, Qilin Xu, Wonse Park, Sumin Lee, Akihiro Furuhashi, Anh D Le
: : Regeneration of peripheral nerve injury remains a major clinical challenge. Recently, mesenchymal stem cells (MSCs) have been considered as potential candidates for peripheral nerve regeneration; however, the underlying mechanisms remain elusive. Here, we show that human gingiva-derived MSCs (GMSCs) could be directly induced into multipotent NPCs (iNPCs) under minimally manipulated conditions without the introduction of exogenous genes. Using a crush-injury model of rat sciatic nerve, we demonstrate that GMSCs transplanted to the injury site could differentiate into neuronal cells, whereas iNPCs could differentiate into both neuronal and Schwann cells...
September 7, 2016: Stem Cells Translational Medicine
Ying Chen, Jiali Pu, Baorong Zhang
Neurodegenerative diseases are characterized by protein aggregation and progressive degeneration of neurons, causing severe functional deficiency in cognition, behavior, and movement. Until now, there has been no effective treatment available in the clinic. Considering the selective loss of specific neurons in the human brain in the pathogenesis of these diseases, generating functional neurons in vitro or in vivo to replace the lost neurons represents a novel strategy to treat neurodegenerative diseases. Human embryonic stem cells and induced pluripotent stem cells have good potential for cell replacement therapy...
August 26, 2016: Human Gene Therapy
Dana M Cairns, Karolina Chwalek, Yvonne E Moore, Matt R Kelley, Rosalyn D Abbott, Stephen Moss, David L Kaplan
Limited availability of human neurons poses a significant barrier to progress in biological and preclinical studies of the human nervous system. Current stem cell-based approaches of neuron generation are still hindered by prolonged culture requirements, protocol complexity, and variability in neuronal differentiation. Here we establish stable human induced neural stem cell (hiNSC) lines through the direct reprogramming of neonatal fibroblasts and adult adipose-derived stem cells. These hiNSCs can be passaged indefinitely and cryopreserved as colonies...
September 13, 2016: Stem Cell Reports
S Grealish, J Drouin-Ouellet, M Parmar
The adult brain has a very limited capacity for generation of new neurons, and neurogenesis only takes place in restricted regions. Some evidence for neurogenesis after injury has been reported, but few, if any, neurons are replaced after brain injury or degeneration, and the permanent loss of neurons leads to long-term disability and loss of brain function. For decades, researchers have been developing cell transplantation using exogenous cell sources for brain repair, and this method has now been shown to successfully restore lost function in experimental and clinical trials...
September 2016: Journal of Internal Medicine
Joshua B Black, Andrew F Adler, Hong-Gang Wang, Anthony M D'Ippolito, Hunter A Hutchinson, Timothy E Reddy, Geoffrey S Pitt, Kam W Leong, Charles A Gersbach
Overexpression of exogenous fate-specifying transcription factors can directly reprogram differentiated somatic cells to target cell types. Here, we show that similar reprogramming can also be achieved through the direct activation of endogenous genes using engineered CRISPR/Cas9-based transcriptional activators. We use this approach to induce activation of the endogenous Brn2, Ascl1, and Myt1l genes (BAM factors) to convert mouse embryonic fibroblasts to induced neuronal cells. This direct activation of endogenous genes rapidly remodeled the epigenetic state of the target loci and induced sustained endogenous gene expression during reprogramming...
September 1, 2016: Cell Stem Cell
Hengzhu Zhang, Min Wei, Yangyang Jiang, Xiaodong Wang, Lei She, Zhengcun Yan, Lun Dong, Lujun Pang, Xingdong Wang
Induced-resembled neuronal cells (irNCs) are generated by reprogramming human melanoma cells through the introduction of key transcription factors, providing novel concepts in the treatment of malignant tumor cells and making it possible to supply neural cells for laboratory use. In the present study, irNCs were derived from A375 cells by inducing the 'forced' overexpression of specific genes, including achaete‑scute homolog 1 (Ascl1), neuronal differentiation factor 1 (Neurod1), myelin transcription factor 1 (Myt1), brain protein 2 (Brn2, also termed POU3F2) and human brain‑derived neurotrophic factor (h‑BDNF)...
October 2016: Molecular Medicine Reports
Demetris Iacovides, Gizem Rizki, Georgios Lapathitis, Katerina Strati
The insufficient ability of specialized cells such as neurons, cardiac myocytes, and epidermal cells to regenerate after tissue damage poses a great challenge to treat devastating injuries and ailments. Recent studies demonstrated that a diverse array of cell types can be directly derived from embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), or somatic cells by combinations of specific factors. The use of iPSCs and direct somatic cell fate conversion, or transdifferentiation, holds great promise for regenerative medicine as these techniques may circumvent obstacles related to immunological rejection and ethical considerations...
2016: Stem Cell Research & Therapy
Giacomo Masserdotti, Sergio Gascón, Magdalena Götz
The key signalling pathways and transcriptional programmes that instruct neuronal diversity during development have largely been identified. In this Review, we discuss how this knowledge has been used to successfully reprogramme various cell types into an amazing array of distinct types of functional neurons. We further discuss the extent to which direct neuronal reprogramming recapitulates embryonic development, and examine the particular barriers to reprogramming that may exist given a cell's unique developmental history...
July 15, 2016: Development
Henrik Ahlenius, Soham Chanda, Ashley E Webb, Issa Yousif, Jesse Karmazin, Stanley B Prusiner, Anne Brunet, Thomas C Südhof, Marius Wernig
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...
July 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
Takanori Eguchi, Takuo Kuboki
Development of human bodies, organs, and tissues contains numerous steps of cellular differentiation including an initial zygote, embryonic stem (ES) cells, three germ layers, and multiple expertized lineages of cells. Induced pluripotent stem (iPS) cells have been recently developed using defined reprogramming factors such as Nanog, Klf5, Oct3/4 (Pou5f1), Sox2, and Myc. This outstanding innovation is largely changing life science and medicine. Methods of direct reprogramming of cells into myocytes, neurons, chondrocytes, and osteoblasts have been further developed using modified combination of factors such as N-myc, L-myc, Sox9, and microRNAs in defined cell/tissue culture conditions...
2016: Stem Cells International
Yoonhee Jin, Jungmok Seo, Jung Seung Lee, Sera Shin, Hyun-Ji Park, Sungjin Min, Eunji Cheong, Taeyoon Lee, Seung-Woo Cho
Triboelectric nanogenerators (TENGs) can be an effective cell reprogramming platform for producing functional neuronal cells for therapeutic applications. Triboelectric stimulation accelerates nonviral direct conversion of functional induced neuronal cells from fibroblasts, increases the conversion efficiency, and induces highly matured neuronal phenotypes with improved electrophysiological functionalities. TENG devices may also be used for biomedical in vivo reprogramming.
September 2016: Advanced Materials
Jin Wan, Daniel Goldman
Unlike mammals, zebrafish are able to regenerate a damaged retina. Key to this regenerative response are Müller glia that respond to retinal injury by undergoing a reprogramming event that allows them to divide and generate a retinal progenitor that is multipotent and responsible for regenerating all major retinal neuron types. The fish and mammalian retina are composed of similar cell types with conserved function. Because of this it is anticipated that studies of retina regeneration in fish may suggest strategies for stimulating Müller glia reprogramming and retina regeneration in mammals...
June 6, 2016: Current Opinion in Genetics & Development
Barbara Treutlein, Qian Yi Lee, J Gray Camp, Moritz Mall, Winston Koh, Seyed Ali Mohammad Shariati, Sopheak Sim, Norma F Neff, Jan M Skotheim, Marius Wernig, Stephen R Quake
Direct lineage reprogramming represents a remarkable conversion of cellular and transcriptome states. However, the intermediate stages through which individual cells progress during reprogramming are largely undefined. Here we use single-cell RNA sequencing at multiple time points to dissect direct reprogramming from mouse embryonic fibroblasts to induced neuronal cells. By deconstructing heterogeneity at each time point and ordering cells by transcriptome similarity, we find that the molecular reprogramming path is remarkably continuous...
June 16, 2016: Nature
Nicole T Jiam, Monica S Pearl, Courtney Carver, Charles J Limb
OBJECTIVE: This study aims to identify electrode contact location and to assess frequency deviation between predicted and actual frequency allocation maps in cochlear implant (CI) users. STUDY DESIGN AND METHODS: This is a retrospective clinical study. Flat-panel computed tomography (FPCT) scans were collected for 17 CI users. Cochlear length was measured using three-dimensional curved multiplanar reconstruction on high-resolution secondary reconstructions. Each electrode's percentage of distance from the base of the helicotrema was measured, and a modified Greenwood's function was applied...
July 2016: Otology & Neurotology
Jie Zheng, Kyung-Ah Choi, Phil Jun Kang, Solji Hyeon, Suhyun Kwon, Jai-Hee Moon, Insik Hwang, Yang In Kim, Yoon Sik Kim, Byung Sun Yoon, Gyuman Park, JangBo Lee, SungHoi Hong, Seungkwon You
The generation of induced neural stem cells (iNSCs) from somatic cells using defined factors provides new avenues for basic research and cell therapies for various neurological diseases, such as Parkinson's disease, Huntington's disease, and spinal cord injuries. However, the transcription factors used for direct reprogramming have the potential to cause unexpected genetic modifications, which limits their potential application in cell therapies. Here, we show that a combination of four chemical compounds resulted in cells directly acquiring a NSC identity; we termed these cells chemically-induced NSCs (ciNSCs)...
May 17, 2016: Biochemical and Biophysical Research Communications
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