Mechanistic Insights Into MicroRNA-Induced Neuronal Reprogramming of Human Adult Fibroblasts

Lu, Ya Lin; Yoo, Andrew S.

doi:10.3389/fnins.2018.00522

Cited by 32 publications

(20 citation statements)

References 97 publications

(144 reference statements)

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“…In this study, we aimed to manipulate transient gene expression and develop a method that can accelerate functional maturity while maintaining high purity induction of neurons with Ngn2 expression. Here, we focused on microRNA-9/9* (miR-9/9*) and microRNA-124 (miR-124), which have been implicated in efficient neuronal differentiation and functional maturity [13,14]. miR-9/9* and miR-124 function as a molecular switch of chromatin modifiers and antagonize anti-neurogenic pathways by suppressing USP14, leading to the destabilization of EZH2 and REST, which is then accompanied by dynamic changes in chromatin structure [15,16].…”

Section: Introductionmentioning

confidence: 99%

miRNA-Based Rapid Differentiation of Purified Neurons from hPSCs Advancestowards Quick Screening for Neuronal Disease Phenotypes In Vitro

Ishikawa

Aoyama

Shibata

et al. 2020

Cells

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Obtaining differentiated cells with high physiological functions by an efficient, but simple and rapid differentiation method is crucial for modeling neuronal diseases in vitro using human pluripotent stem cells (hPSCs). Currently, methods involving the transient expression of one or a couple of transcription factors have been established as techniques for inducing neuronal differentiation in a rapid, single step. It has also been reported that microRNAs can function as reprogramming effectors for directly reprogramming human dermal fibroblasts to neurons. In this study, we tested the effect of adding neuronal microRNAs, miRNA-9/9*, and miR-124 (miR-9/9*-124), for the neuronal induction method of hPSCs using Tet-On-driven expression of the Neurogenin2 gene (Ngn2), a proneural factor. While it has been established that Ngn2 can facilitate differentiation from pluripotent stem cells into neurons with high purity due to its neurogenic effect, a long or indefinite time is required for neuronal maturation with Ngn2 misexpression alone. With the present method, the cells maintained a high neuronal differentiation rate while exhibiting increased gene expression of neuronal maturation markers, spontaneous calcium oscillation, and high electrical activity with network bursts as assessed by a multipoint electrode system. Moreover, when applying this method to iPSCs from Alzheimer’s disease (AD) patients with presenilin-1 (PS1) or presenilin-2 (PS2) mutations, cellular phenotypes such as increased amount of extracellular secretion of amyloid β42, abnormal oxygen consumption, and increased reactive oxygen species in the cells were observed in a shorter culture period than those previously reported. Therefore, it is strongly anticipated that the induction method combining Ngn2 and miR-9/9*-124 will enable more rapid and simple screening for various types of neuronal disease phenotypes and promote drug discovery.

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Section: Introductionmentioning

confidence: 99%

miRNA-Based Rapid Differentiation of Purified Neurons from hPSCs Advancestowards Quick Screening for Neuronal Disease Phenotypes In Vitro

Ishikawa

Aoyama

Shibata

et al. 2020

Cells

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“…Here we will discuss recent reprogramming studies in conversion of cell lineages, with a focus on transcription factor-based reprogramming studies. However, it should be noted that other reprogramming approaches have also been described, such as the use of microRNA and small molecules for cellular reprogramming which were reviewed in details recently by others ( Janowska et al, 2018 ; Li et al, 2018 ; Lu and Yoo, 2018 ).…”

Section: Direct Reprogramming To Generate Neurons In Vitro mentioning

confidence: 99%

Potentials of Cellular Reprogramming as a Novel Strategy for Neuroregeneration

Fang

Wazan

Tan

et al. 2018

Front. Cell. Neurosci.

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Cellular reprogramming technology holds great potential for tissue repair and regeneration to replace cells that are lost due to diseases or injuries. In addition to the landmark discovery of induced pluripotent stem cells, advances in cellular reprogramming allow the direct lineage conversion of one somatic cell type to another using defined transcription factors. This direct reprogramming technology represents a rapid way to generate target cells in the laboratory, which can be used for transplantation and studies of biology and diseases. More importantly, recent work has demonstrated the exciting application of direct reprogramming to stimulate regeneration in vivo, providing an alternative approach to transplantation of donor cells. Here, we provide an overview of the underlying concept of using cellular reprogramming to convert cell fates and discuss the current advances in cellular reprogramming both in vitro and in vivo, with particular focuses on the neural and retinal systems. We also discuss the potential of in vivo reprogramming in regenerative medicine, the challenges and potential solutions to translate this technology to the clinic.

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“…MicroRNAs regulate not only the expression of genes and proteins but also act as epigenetic factors. Many studies have shown that microRNAs have the property of directly affecting the subunits of chromatin remodeling complexes associated with ATP-dependent BRG/BRM factor (BAF), which is critical for neuron differentiation (Staahl et al, 2013;Abernathy et al, 2017;Lu and Yoo, 2018). MicroRNAs are used in combinations with various transcription factors in direct reprogramming of somatic cells into neurons (Yoo et al, 2011).…”

Section: Alternative Methods For Geneticmentioning

confidence: 99%

Reprogramming of Differentiated Mammalian and Human Retinal Pigment Epithelium: Current Achievements and Prospects

2020

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Impairment of the homeostatic and functional integrity of the retina and retinal pigment epithelium (RPE) is the main cause of some degenerative diseases of the human eye, which are accompanied by loss of eyesight. Despite the significant progress made over the past decades in the development of new methods for treatment for this pathology, there are still several complications when using surgical methods for correction of eyesight and so far insurmountable limitations in the applications of modern approaches, such as gene therapy and genetic engineering. One of the promising approaches to the treatment of degenerative diseases of the retina may be an approach based on the application of regenerative capacities of its endogenous cells with high plasticity, in particular, of RPE cells and Müller glia. Currently, vertebrate RPE cells are of great interest as a source of new photoreceptors and other neurons in the degrading retina in vivo. In this regard, the possibilities of their direct reprogramming by genetic, epigenetic, and chemical methods and their combination are being investigated. This review focuses on research in gene-directed reprogramming of vertebrate RPE cells into retinal neurons, with detailed analysis of the genes used as the main reprogramming factors, comparative analysis, and extrapolation of experimental data from animals to humans. Also, this review covers studies on the application of alternative approaches to gene-directed reprogramming, such as chemicalmediated reprogramming with the use of cocktails of therapeutic low-molecular-weight compounds and microRNAs. In general, the research results indicate the complexity of the process for direct reprogramming of human RPE cells into retinal neurons. However, taking into account the results of direct reprogramming of vertebrate cells and the accessibility of human RPE cells for various vectors that deliver a variety of molecules to cells, such as transcription factors, chimeric endonucleases, recombinant proteins, and low-weight molecular compounds, the most optimal combination of factors for the successful conversion of human RPE cells to retinal neurons can be suggested.

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Mechanistic Insights Into MicroRNA-Induced Neuronal Reprogramming of Human Adult Fibroblasts

Cited by 32 publications

References 97 publications

miRNA-Based Rapid Differentiation of Purified Neurons from hPSCs Advancestowards Quick Screening for Neuronal Disease Phenotypes In Vitro

miRNA-Based Rapid Differentiation of Purified Neurons from hPSCs Advancestowards Quick Screening for Neuronal Disease Phenotypes In Vitro

Potentials of Cellular Reprogramming as a Novel Strategy for Neuroregeneration

Reprogramming of Differentiated Mammalian and Human Retinal Pigment Epithelium: Current Achievements and Prospects

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