Generation of dopamine neuronal-like cells from induced neural precursors derived from adult human cells by non-viral expression of lineage factors

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Show simple item record Playne, R en Jones, Kathryn en Connor, Bronwen en 2020-04-09T00:57:54Z en 2018-01-01 en
dc.identifier.citation Journal of Stem Cells and Regenerative Medicine 14(1):P34-P44 01 Jan 2018 en
dc.identifier.issn 0973-7154 en
dc.identifier.uri en
dc.description.abstract Reprogramming technology holds great promise for the study and treatment of Parkinson’s disease (PD) as patient-specific ventral midbrain dopamine (vmDA) neurons can be generated. This should facilitate the investigation of early changes occurring during PD pathogenesis, permitting the identification of new drug targets and providing a platform for drug screening. To date, most studies using reprogramming technology to study PD have employed induced pluripotent stem cells. Research into PD using direct reprogramming has been limited due to an inability to generate high yields of authentic human vmDA neurons. Nevertheless, direct reprogramming offers a number of advantages, and development of this technology is warranted. Previous reports have indicated that induced neural precursors (iNPs) derived from adult human fibroblasts by lineage factor-mediated direct reprogramming can give rise to dopamine neurons expressing tyrosine hydroxylase (TH+). Using normal adult human fibroblasts, the present study aimed to extend these findings and determine the capacity of iNPs for generating vmDA neurons, with the aim of utilising this technology for the future study of PD. While iNPs expressed late vmDA fate markers such as NURR1 and PITX3, critical early regional markers LMX1A, FOXA2 and EN1 were not expressed. Upon differentiation, iNPs gave rise to dopamine neuronal-like cells expressing TUJ1, TH, AADC, DAT, VMAT2 and GIRK2. To induce an authentic A9 phenotype, a series of experiments investigated temporal exposure to patterning factors. Exposure to SHH-C24II, purmorphamine, CHIR99021 and/or FGF8b during or after reprogramming was insufficient to induce expression of early vmDA regional markers. Addition of LMX1A/FOXA2 to the transfection cocktail did not induce a sustained vmDA iNP phenotype. This study reports for the first time that iNPs derived from healthy adult human cells by non-viral expression of lineage factors can give rise to dopamine neuronal-like cells. Direct-to-iNP reprogramming could be a suitable strategy for modelling PD in vitro using aged donor-derived cells. en
dc.language English en
dc.publisher German Stem Cell Society en
dc.relation.ispartofseries Journal of Stem Cells and Regenerative Medicine en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.rights.uri en
dc.subject Science & Technology en
dc.subject Life Sciences & Biomedicine en
dc.subject Cell & Tissue Engineering en
dc.subject Cell Biology en
dc.subject Induced neural precursor cells en
dc.subject Dopamine neurons en
dc.subject Direct reprogramming en
dc.subject Adult human fibroblasts en
dc.subject Parkinson's disease en
dc.subject SMALL MOLECULES en
dc.subject PROGENITOR CELLS en
dc.subject HUMAN ES en
dc.title Generation of dopamine neuronal-like cells from induced neural precursors derived from adult human cells by non-viral expression of lineage factors en
dc.type Journal Article en
pubs.issue 1 en
pubs.begin-page P34 en
pubs.volume 14 en
dc.rights.holder Copyright: Journal of Stem Cells and Regenerative Medicine en en
pubs.end-page P44 en
pubs.publication-status Published en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 744779 en Medical and Health Sciences en Medical Sciences en Pharmacology en Science en Biological Sciences en
pubs.record-created-at-source-date 2020-05-29 en

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