Induction of Functional Dopamine Neurons from Human Astrocytes in Vitro and Mouse Astrocytes in a Parkinson's Disease Model

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2017 Apr 12

PMID 28398344

Citations 171

Authors

Pia Rivetti di Val Cervo

Roman A Romanov

Giada Spigolon

Debora Masini

Elisa Martin-Montanez

Enrique M Toledo

Gioele La Manno

Michael Feyder

Christian Pifl

Yi-Han Ng

Sara Padrell Sanchez

Sten Linnarsson

Marius Wernig

Tibor Harkany

Gilberto Fisone

Ernest Arenas

Affiliations

Soon will be listed here.

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.

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