1. Neuroprotection of host cells by human central nervous system stem cells in a mouse model of infantile neuronal ceroid lipofuscinosis.
- Author
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Tamaki SJ, Jacobs Y, Dohse M, Capela A, Cooper JD, Reitsma M, He D, Tushinski R, Belichenko PV, Salehi A, Mobley W, Gage FH, Huhn S, Tsukamoto AS, Weissman IL, and Uchida N
- Subjects
- Animals, Brain enzymology, Brain pathology, Cell Differentiation, Cell Movement, Cell Survival, Disease Models, Animal, Endocytosis, Fibroblasts cytology, Fibroblasts enzymology, Fluorescence, Humans, Inflammation complications, Inflammation pathology, Intracellular Space enzymology, Lipofuscin metabolism, Mice, Motor Activity, Mutation genetics, Nerve Degeneration complications, Nerve Degeneration pathology, Nerve Degeneration physiopathology, Neuronal Ceroid-Lipofuscinoses complications, Neuronal Ceroid-Lipofuscinoses physiopathology, Neurons enzymology, Receptor, IGF Type 2 metabolism, Stem Cell Transplantation, Stem Cells metabolism, Thiolester Hydrolases deficiency, Thiolester Hydrolases metabolism, Central Nervous System cytology, Cytoprotection, Neuronal Ceroid-Lipofuscinoses pathology, Neuronal Ceroid-Lipofuscinoses therapy, Neurons cytology, Stem Cells cytology
- Abstract
Infantile neuronal ceroid lipofuscinosis (INCL) is a fatal neurodegenerative disease caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). Ppt1 knockout mice display hallmarks of INCL and mimic the human pathology: accumulation of lipofuscin, degeneration of CNS neurons, and a shortened life span. Purified non-genetically modified human CNS stem cells, grown as neurospheres (hCNS-SCns), were transplanted into the brains of immunodeficient Ppt1(-/)(-) mice where they engrafted robustly, migrated extensively, and produced sufficient levels of PPT1 to alter host neuropathology. Grafted mice displayed reduced autofluorescent lipofuscin, significant neuroprotection of host hippocampal and cortical neurons, and delayed loss of motor coordination. Early intervention with cellular transplants of hCNS-SCns into the brains of INCL patients may supply a continuous and long-lasting source of the missing PPT1 and provide some therapeutic benefit through protection of endogenous neurons. These data provide the experimental basis for human clinical trials with these banked hCNS-SCns.
- Published
- 2009
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