Transplantation and magnetic resonance imaging of canine neural progenitor cell grafts in the postnatal dog brain.

Cellular transplantation in the form of bone marrow has been one of the primary treatments of many lysosomal storage diseases (LSDs). Although bone marrow transplantation can help central nervous system manifestations in some cases, it has little impact in many LSD patients. Canine models of neurogenetic LSDs provide the opportunity for modeling central nervous system transplantation strategies in brains that more closely approximate the size and architectural complexity of the brains of children. Canine olfactory bulb-derived neural progenitor cells (NPCs) isolated from dog brains were expanded ex vivo and implanted into the caudate nucleus/thalamus or cortex of allogeneic dogs. Canine olfactory bulb-derived NPCs labeled with micron-sized superparamagnetic iron oxide particles were detected by magnetic resonance imaging both in vivo and postmortem. Grafts expressed markers of NPCs (i.e. nestin and glial fibrillary acidic protein), but not the neuronal markers Map2ab or beta-tubulin III. The NPCs were from dogs with the LSD mucopolysaccharidosis VII, which is caused by a deficiency of beta-glucuronidase. When mucopolysaccharidosis VII canine olfactory bulb-NPCs that were genetically corrected with a lentivirus vector ex vivo were transplanted into mucopolysaccharidosis VII recipient brains, they were detected histologically by beta-glucuronidase expression in areas identified by antemortem magnetic resonance imaging tracking. These results demonstrate the potential for ex vivo stem cell-based gene therapy and noninvasive tracking of therapeutic grafts in vivo.

Structure-specific patterns of neural stem cell engraftment after transplantation in the adult mouse brain.

Transplantation of neural stem cells (NSCs) may be useful for delivering exogenous gene products to the diseased CNS. When NSCs are transplanted into the developing mouse brain, they can migrate extensively and differentiate into cells appropriate to the sites of engraftment, in response to the normal signals directing endogenous cells to their appropriate fates. Much of the prior work on NSC migration in the adult brain has examined directed migration within or toward focal areas of injury such as ischemia, brain tumors, or 6-hydroxydopamine (6-OHDA) lesions. However, treatment of many genetic disorders that affect the CNS will require widespread dissemination of the donor cells in the postnatal brain, because the lesions are typically distributed globally. We therefore tested the ability of NSCs to migrate in the unlesioned adult mouse brain after stereotaxic transplantation into several structures including the cortex and hippocampus. NSC engraftment was monitored in live animals by magnetic resonance imaging (MRI) after superparamagnetic iron oxide (SPIO) labeling of cells. Histological studies demonstrated that the cells engrafted in significantly different patterns within different regions of the brain. In the cerebral cortex, donor cells migrated in all directions from the injection site. The cells maintained an immature phenotype and cortical migration was enhanced by trypsin treatment of the cells, indicating a role for cell surface proteins. In the hippocampus, overall cell survival and migration were lower but there was evidence of neuronal differentiation. In the thalamus, the transplanted cells remained in a consolidated mass at the site of injection. These variations in pattern of engraftment should be taken into account when designing treatment approaches in nonlesion models of neurologic disease.