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Fate of Immortalized Human Neuronal Progenitor Cells Transplanted in Rat Spinal Cord
Peiying Li, MD;
Alan Tessler, MD;
Steve S. W. Han, PhD;
Itzhak Fischer, PhD;
Mahendra S. Rao, PhD;
Michael E. Selzer, MD, PhD
Arch Neurol. 2005;62:223-229.
Background Replacement of neurons and glia by transplantation has been proposed as a therapy for neurodegenerative diseases, including amyotrophic lateral sclerosis. This strategy requires using human motor neuronal progenitor cells or xenografts of animal cells, but there is little evidence that xenografted neuronal cells can survive in spinal cord despite immunosuppression.
Objective To clarify the mechanisms responsible for the death of xenografted neurons in spinal cord.
Methods Cells from an immortalized, neuronally committed, human embryonic spinal cord–derived cell line (HSP1) that expresses motor neuronal properties in vitro were transplanted into adult rat spinal cord. The rats were killed at intervals up to 8 weeks and serial sections through the graft sites were processed for immunofluorescence using primary antibodies against human nuclear and mitochondrial antigens, microtubule-associated protein 2, TUJ1, CD5, natural killer cells, and activated microglia-macrophages, caspase-3 and caspase-9.
Results Grafted cells did not migrate and underwent partial differentiation along a neuronal pathway. They were rejected after 4 weeks despite cyclosporine immunosuppression. Cells died by apoptosis via the cytochrome c/caspase-9/caspase-3 pathway. The host response included natural killer cells and activated microglia-macrophages but few T cells.
Conclusions Intraspinal neuronal xenotransplantation failed because of apoptotic cell death. Neither T cells nor the spinal cord environment, which favors gliogenesis, are likely to have been responsible, but natural killer cells may have been involved.
Author Affiliations: Department of Neurology and the David Mahoney Institute of Neurological Sciences, University of Pennsylvania Medical Center (Drs Li and Selzer); Department of Veterans Affairs Hospital (Dr Tessler); Department of Neurobiology and Anatomy, Drexel University College of Medicine (Drs Tessler, Han, and Fischer), Philadelphia; and the Gerontology Research Center, Laboratory of Neuroscience, National Institute on Aging, Baltimore, Md (Dr Rao).
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