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The Journal of Neuroscience, November 15, 2006, 26(46):11948-11960; doi:10.1523/JNEUROSCI.3127-06.2006

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Development/Plasticity/Repair
Growth Factor Treatment and Genetic Manipulation Stimulate Neurogenesis and Oligodendrogenesis by Endogenous Neural Progenitors in the Injured Adult Spinal Cord

Yasuo Ohori,^1,3,4 Shin-ichi Yamamoto,^3,4 Motoshi Nagao,¹ Michiya Sugimori,¹ Naoya Yamamoto,⁴ Kozo Nakamura,³ and Masato Nakafuku^1,2,5

¹Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio 45229-3039, ²Departments of Pediatrics and Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521, ³Department of Orthopaedic Surgery, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-0033, Japan, ⁴Division of Motor Dysfunction, Research Institute, National Rehabilitation Center, Tokorozawa, Saitama 359-8555, Japan, and ⁵Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Chuo-ku, Tokyo 103-0027, Japan

Correspondence should be addressed to Dr. Masato Nakafuku, Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229-3039. Email: masato.nakafuku{at}cchmc.org

Neurons and oligodendrocytes are highly vulnerable to various insults, and their spontaneous replacement occurs to only a limited extent after damage in the adult spinal cord. The environment of injured tissue is thus thought to restrict the regenerative capacity of endogenous neural stem/progenitor cells; strategies for overcoming such restrictions remain to be developed. Here, we combined growth factor treatment and genetic manipulation to stimulate neurogenesis and oligodendrogenesis by endogenous progenitors in vivo. The recombinant retrovirus pMXIG, which was designed to coexpress green fluorescent proteins (GFPs) and a neurogenic/gliogenic transcription factor, was directly injected into the injured spinal cord parenchyma to manipulate proliferative cells in situ. We found that cells expressing Olig2, Nkx2.2, and NG2 were enriched among virus-infected, GFP-positive (GFP⁺) cells. Moreover, a fraction of GFP⁺ cells formed neurospheres and differentiated into neurons, astrocytes, and oligodendrocytes in vitro, demonstrating that GFP retroviruses indeed infected endogenous neural progenitors in vivo. Neuronal differentiation of control virus-infected cells did not occur at a detectable level in the injured spinal cord. We found, however, that direct administration of fibroblast growth factor 2 and epidermal growth factor into lesioned tissue could induce a significant fraction of GFP-labeled cells to express immature neuronal markers. Moreover, retrovirus-mediated overexpression of the basic helix-loop-helix transcription factors Neurogenin2 and Mash1, together with growth factor treatment, enhanced the production and maturation of new neurons and oligodendrocytes, respectively. These results demonstrate that endogenous neural progenitors can be manipulated to replace neurons and oligodendrocytes lost to insults in the injured spinal cord.

Key words: stem cell; regeneration; repair; spinal cord injury; neurogenesis; oligodendrocyte; bHLH factor; growth factor

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Received Jan. 11, 2006; revised Sept. 5, 2006; accepted Oct. 10, 2006.

Correspondence should be addressed to Dr. Masato Nakafuku, Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229-3039. Email: masato.nakafuku{at}cchmc.org

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