期刊
STEM CELLS
卷 27, 期 9, 页码 2362-2370出版社
WILEY
DOI: 10.1002/stem.163
关键词
Neural stem cell therapy; Lysosomal storage disorders; Sandhoff disease; Neurodegenerative disease; Metabolic cross-correction; Adult brain; Behavior chemokines; Migration; Magnetic Resonance Imaging; Inflammation
资金
- National Institute of General Medicine [NIH P20 GM075059]
- National Institute of Neurological Diseases Stroke [5 R01 NS055195-04]
- California Institute for Regenerative Medicine
- Sanford Center for Child Health Research
- Children's Neurobiological Solutions
- Legler-Benbough Foundation
- Vertebi Foundation
- Margot Anderson Brain Research Trust
- Schutz Foundation
- MRC [G0400834] Funding Source: UKRI
- Medical Research Council [G0400834] Funding Source: researchfish
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P20GM075059] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R56NS055195, R01NS055195] Funding Source: NIH RePORTER
Although we and others have demonstrated that neural stem cells (NSCs) may impact such neurogenetic conditions as lysosomal storage diseases when transplanted at birth, it has remained unclear whether such interventions can impact well-established mid-stage disease, a situation often encountered clinically. Here we report that when NSCs were injected intracranially into the brain of adult symptomatic Sandhoff (Hexb(-/-)) mice, cells migrated far from the injection site and integrated into the host cytoarchitecture, restoring beta-hexosaminidase enzyme activity and promoting neuropathologic and behavioral improvement. Mouse lifespan increased, neurological function improved, and disease progression was slowed. These clinical benefits correlated with neuropathological correction at the cellular and molecular levels, reflecting the multiple potential beneficial actions of stem cells, including enzyme cross-correction, cell replacement, tropic support, and direct anti-inflammatory action. Pathotropism (i.e., migration and homing of NSCs to pathological sites) could be imaged in real time by magnetic resonance imaging. Differentially expressed chemokines might play a role in directing the migration of transplanted stem cells to sites of pathology. Significantly, the therapeutic impact of NSCs implanted in even a single location was surprisingly widespread due to both cell migration and enzyme diffusion. Because many of the beneficial actions of NSCs observed in newborn brains were recapitulated in adult brains to the benefit of Sandhoff recipients, NSC-based interventions may also be useful in symptomatic subjects with established disease. STEM CELLS 2009; 27: 2362-2370
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