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Transplantation of Embryonic Stem Cells Improves Nerve Repair and Functional Recovery after Severe Sciatic Nerve Axotomy in Rats.

Cui L, Jiang J, Wei L, Zhou X, Fraser JL, Snider BJ, Yu SP

*Department of Pathology andDepartment of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina, USA;Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China; andDepartment of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.

Nerve regeneration and repair are critical for functional restoration after injury in the central as well as peripheral nervous system. Extensive research in recent years has focused on transplantation of multipotent stem cells for the treatment of central nervous system disorders, but the potential therapeutic benefits of stem cell transplantation for injured peripheral nerves have remained largely uninvestigated. We used a rat sciatic nerve transection model to test the ability of implanted embryonic stem (ES) cells to promote repair of a severely injured peripheral nerve. Mouse ES cells were neurally induced in vitro by a retinoic acid protocol; enhanced expression and/or secretion of several growth factors were detected in differentiating ES cells. One hour after removal of a 1 cm segment of the left sciatic nerve, neurally induced ES cells were implanted into the gap between the nerve stumps with the surrounding epineurium as a natural conduit. The ES cell transplantation resulted in substantial axonal regrowth and nerve repair, which were not seen in culture medium implant controls. One to three months after axotomy, coimmunostaining with the mouse neural cell membrane specific antibody M2/M6 and the Schwann cell marker S100 suggested that transplanted ES cells had survived and differentiated into myelinating cells. Regenerated axons were myelinated and showed uniform connections between proximal and distal stumps. Nerve stumps had near normal diameter and appeared healthy with longitudinally oriented, densely packed Schwann cell-like phenotype, mainly in the proximal stump. Fluoro-Gold retrograde-labeled neurons were found in the spinal cord (T12-13) and dorsal root ganglia (L4-L6) after ES cell transplantation, suggesting reconnection of axons across the transection. Electrophysiological recordings showed functional activity recovered across the injury gap. These data suggest that transplanted neurally induced ES cells differentiate into myelin-forming cells and provide a potential therapy for severely injured peripheral nerves.--Cui, L., Jiang, J., Wei, L., Zhou, X., Fraser, J. L., Snider, B. J., Gottlieb, D. I., Yu, S. P. Transplantation of embryonic stem cells improves nerve repair and functional recovery after severe sciatic nerve axotomy in rats.

Published 3 April 2007 in FASEB J.
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