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TISSUE-SPECIFIC STEM CELLS

Directed Evolution of Motor Neurons from Genetically Engineered Neural Precursors

^aInstitut Pasteur, Institut National de la Santé et de la Recherche Médicale U622, Unité Rétrovirus et Transfert Génétique, Paris, France;
^bInstitut National de la Santé et de la Recherche Médicale, Université de la Méditerranée, Equipe Avenir, Dégénérescence et Protection Axonale, Marseille, France

Key Words. Neural stem cell • Neural differentiation • Transcription factors • Transplantation • Motor neurons • Spinal cord • Neurodegenerative diseases

Correspondence: Correspondence: Delphine Bohl, Ph.D.,Unité Rétrovirus et Transfert Génétique, U622 INSERM, Département Neuroscience, Institut Pasteur, 28 rue du Dr. Roux, 75015 Paris, France. Telephone: 33-1-45688412; Fax: 33-1-45688940; e-mail: dbohl{at}pasteur.fr

Received on April 14, 2008; accepted for publication on July 7, 2008.

First published online in STEM CELLS EXPRESS  July 17, 2008.

Stem cell-based therapies hold therapeutic promise for degenerative motor neuron diseases, such as amyotrophic lateral sclerosis, and for spinal cord injury. Fetal neural progenitors present less risk of tumor formation than embryonic stem cells but inefficiently differentiate into motor neurons, in line with their low expression of motor neuron-specific transcription factors and poor response to soluble external factors. To overcome this limitation, we genetically engineered fetal rat spinal cord neurospheres to express the transcription factors HB9, Nkx6.1, and Neurogenin2. Enforced expression of the three factors rendered neural precursors responsive to Sonic hedgehog and retinoic acid and directed their differentiation into cholinergic motor neurons that projected axons and formed contacts with cocultured myotubes. When transplanted in the injured adult rat spinal cord, a model of acute motor neuron degeneration, the engineered precursors transiently proliferated, colonized the ventral horn, expressed motor neuron-specific differentiation markers, and projected cholinergic axons in the ventral root. We conclude that genetic engineering can drive the differentiation of fetal neural precursors into motor neurons that efficiently engraft in the spinal cord. The strategy thus holds promise for cell replacement in motor neuron and related diseases.

Disclosure of potential conflicts of interest is found at the end of this article.

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