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      Direct Conversion of Human Urine Cells to Neurons by Small Molecules

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          Abstract

          Transdifferentiation of other cell type into human neuronal cells (hNCs) provides a platform for neural disease modeling, drug screening and potential cell-based therapies. Among all of the cell donor sources, human urine cells (hUCs) are convenient to obtain without invasive harvest procedure. Here, we report a novel approach for the transdifferentiation of hUCs into hNCs. Our study demonstrated that a combination of seven small molecules (CAYTFVB) cocktail induced transdifferentiation of hUCs into hNCs. These chemical-induced neuronal cells (CiNCs) exhibited typical neuron-like morphology and expressed mature neuronal markers. The neuronal-like morphology revealed in day 1, and the Tuj1-positive CiNCs reached to about 58% in day 5 and 38.36% Tuj1+/MAP2+ double positive cells in day 12. Partial electrophysiological properties of CiNCs was obtained using patch clamp. Most of the CiNCs generated using our protocol were glutamatergic neuron populations, whereas motor neurons, GABAergic or dopaminergic neurons were merely detected. hUCs derived from different donors were converted into CiNCs in this work. This method may provide a feasible and noninvasive approach for reprogramming hNCs from hUCs for disease models and drug screening.

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          Direct conversion of fibroblasts to functional neurons by defined factors

          Cellular differentiation and lineage commitment are considered robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2, and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials, and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modeling, and regenerative medicine.
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            Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming.

            Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-wide expression analysis confirmed that treatments promoting neuronal reprogramming elicit an anti-oxidative stress response. Importantly, co-expression of Bcl-2 and anti-oxidative treatments leads to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type in vitro and in vivo.
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              Urine derived cells are a potential source for urological tissue reconstruction.

              Contemporary approaches to tissue engineering and cell therapy for urinary tract reconstruction require invasive tissue biopsies to obtain autologous cells. However, these procedures are associated with potential complications. We determined whether the cells present in urine have characteristics of normal bladder cells and investigated their potential uses for urological reconstructive procedures. A total of 55 urine samples were collected from 15 healthy individuals and 8 patients with vesicoureteral reflux. Urine derived cells were isolated, expanded and tested for progenitor and differentiated cell specific markers using flow cytometry, immunofluorescence and Western immunoblotting. The chromosomal stability of cultured urine derived cells was determined by karyotype analysis. Clones were successfully established from primary cultures of urine derived cells. Isolated cells showed 3 phenotypes, including fully differentiated, differentiating and progenitor-like cells. Some urine derived cells stained positive for the surface markers c-Kit, SSEA4, CD105, CD73, CD91, CD133 and CD44. Two to 7 cells per 100 ml urine were multipoint progenitors that could expand extensively in culture. Single progenitor cells had the ability to differentiate into the cell lineages expressing urothelial, smooth muscle, endothelial and interstitial cell markers. The expression of lineage markers was characterized by Western blot and immunofluorescence analysis. Urine derived cells also maintained a normal karyotype after serial culture. A subpopulation of cells isolated from urine had progenitor cell features and the potential to differentiate into several bladder cell lineages. Urine derived cells could serve as an alternative cell source for urinary tract tissue engineering and reconstruction.
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                Author and article information

                Contributors
                li_yinxiong_iph@gibh.ac.cn
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                13 November 2019
                13 November 2019
                2019
                : 9
                : 16707
                Affiliations
                [1 ]ISNI 0000 0004 1798 2725, GRID grid.428926.3, Institute of Public Health, , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, ; Guangzhou, China
                [2 ]ISNI 0000 0004 1798 2725, GRID grid.428926.3, Guangdong Provincial Key Laboratory of Biocomputing, , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, ; Guangzhou, China
                [3 ]ISNI 0000 0004 1798 2725, GRID grid.428926.3, Key Laboratory of Regenerative Biology, , South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, ; Guangzhou, China
                [4 ]ISNI 0000 0004 1797 8419, GRID grid.410726.6, University of Chinese Academy of Sciences, ; Beijing, China
                [5 ]GRID grid.484195.5, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, ; Guangzhou, China
                [6 ]GRID grid.418339.4, Guangzhou Blood Center, ; Guangzhou, China
                [7 ]ISNI 0000 0004 1760 3828, GRID grid.412601.0, Department of Gastroenterology, , The First Affiliated Hospital of Jinan University, ; Guangzhou, China
                [8 ]Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China
                Article
                53007
                10.1038/s41598-019-53007-6
                6854089
                31723223
                0dd48efd-a97b-4d93-9b74-10b846c2b21c
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 8 April 2019
                : 25 October 2019
                Funding
                Funded by: the National Basic Research Program of China 973 Program (2015CB964700), the Chinese Government Recruitment “Thousand Talents Program” (ODCCC2268) (Yin-xiong Li), the Guangdong Province Science and Technology Plan (2016B030301007, 2015B020230007, 2014B020225004, 2018A050506070), the National Natural Science Foundation of China (31871379), Guangzhou City Science and Technology Plan (201704020212), Frontier Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2018GZR110105011).
                Categories
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                © The Author(s) 2019

                Uncategorized
                cellular neuroscience,transdifferentiation
                Uncategorized
                cellular neuroscience, transdifferentiation

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