Journal ArticleDOI
Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model
Pia Rivetti di Val Cervo,Roman A. Romanov,Roman A. Romanov,Giada Spigolon,Débora Masini,Elisa Martín-Montañez,Enrique M. Toledo,Gioele La Manno,Michael Feyder,Christian Pifl,Yi Han Ng,Sara Padrell Sánchez,Sten Linnarsson,Marius Wernig,Tibor Harkany,Tibor Harkany,Gilberto Fisone,Ernest Arenas +17 more
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TLDR
This work uses three transcription factors, NEUROD1, ASCL1 and LMX1A, and the microRNA miR218 to reprogram human and mouse astrocytes in vitro and in vivo into induced dopamine neurons (iDANs), which may enable clinical therapies for Parkinson's disease by delivery of genes rather than cells.Abstract:
Cell replacement therapies for neurodegenerative disease have focused on transplantation of the cell types affected by the pathological process. Here we describe an alternative strategy for Parkinson's disease in which dopamine neurons are generated by direct conversion of astrocytes. Using three transcription factors, NEUROD1, ASCL1 and LMX1A, and the microRNA miR218, collectively designated NeAL218, we reprogram human astrocytes in vitro, and mouse astrocytes in vivo, into induced dopamine neurons (iDANs). Reprogramming efficiency in vitro is improved by small molecules that promote chromatin remodeling and activate the TGFβ, Shh and Wnt signaling pathways. The reprogramming efficiency of human astrocytes reaches up to 16%, resulting in iDANs with appropriate midbrain markers and excitability. In a mouse model of Parkinson's disease, NeAL218 alone reprograms adult striatal astrocytes into iDANs that are excitable and correct some aspects of motor behavior in vivo, including gait impairments. With further optimization, this approach may enable clinical therapies for Parkinson's disease by delivery of genes rather than cells.read more
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Non-engineered and Engineered Adult Neurogenesis in Mammalian Brains
TL;DR: Compared to cell transplantation or the non-engineered adult neurogenesis, in vivo engineered neuroregeneration technology can provide a large number of functional new neurons in situ to repair damaged brain and spinal cord.
Journal ArticleDOI
Treating Parkinson's disease by astrocyte reprogramming: Progress and challenges.
TL;DR: In this article, a review of the potential, challenges, and potential risks of astrocyte reprogramming for an enduring alleviation of parkinsonian symptoms are conferred.
Journal ArticleDOI
Instructing neuronal identity during CNS development and astroglial-lineage reprogramming: Roles of NEUROG2 and ASCL1
Malek Chouchane,Marcos R. Costa +1 more
TL;DR: It is concluded that Ascl1 and Neurog2 have different contributions to determine neuronal fates, depending on the neural progenitor or astroglial population expressing those proneural factors.
Journal ArticleDOI
Astrocyte dysfunction in Parkinson's disease: from the perspectives of transmitted α-synuclein and genetic modulation
TL;DR: In this article, the authors discuss the role of α-synuclein (α-syn) pathology in Parkinson's disease and conclude that replenishing the glial cells is a valuable therapeutic approach.
Journal ArticleDOI
Novel Tools towards Magnetic Guidance of Neurite Growth: (I) Guidance of Magnetic Nanoparticles into Neurite Extensions of Induced Human Neurons and In Vitro Functionalization with RAS Regulating Proteins.
Hendrik Schöneborn,Fabian Raudzus,Emilie Secret,Nils Otten,Aude Michel,Jérôme Fresnais,Christine Ménager,Jean-Michel Siaugue,Holm Zaehres,Irmgard D. Dietzel,Rolf Heumann +10 more
TL;DR: These results may have relevance for future therapeutic approaches of cell replacement therapy in Parkinson’s disease and developed tools towards remote control of directed neurite growth in human dopaminergic neurons.
References
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Journal ArticleDOI
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TL;DR: This work presents DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates, which enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression.
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Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
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Journal ArticleDOI
Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling
Stuart M. Chambers,Christopher A. Fasano,Eirini P. Papapetrou,Mark J. Tomishima,Michel Sadelain,Lorenz Studer +5 more
TL;DR: Noggin/SB431542-based neural induction should facilitate the use of hES and hiPS cells in regenerative medicine and disease modeling and obviate the need for protocols based on stromal feeders or embryoid bodies.
Journal ArticleDOI
Direct conversion of fibroblasts to functional neurons by defined factors
Thomas Vierbuchen,Austin Ostermeier,Zhiping P. Pang,Yuko Kokubu,Thomas C. Südhof,Marius Wernig +5 more
TL;DR: In this paper, a combination of three transcription factors, Ascl1, Brn2 (also called Pou3f2) and Myt1l, was used to convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro.
Journal ArticleDOI
Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq
Amit Zeisel,Ana B. Muñoz-Manchado,Simone Codeluppi,Peter Lönnerberg,Gioele La Manno,Anna Juréus,Sueli Marques,Hermany Munguba,Liqun He,Christer Betsholtz,Christer Betsholtz,Charlotte Rolny,Gonçalo Castelo-Branco,Jens Hjerling-Leffler,Sten Linnarsson +14 more
TL;DR: Large-scale single-cell RNA sequencing is used to classify cells in the mouse somatosensory cortex and hippocampal CA1 region and found 47 molecularly distinct subclasses, comprising all known major cell types in the cortex.
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