When considering the surgical transplantation method, it is imperative to understand the mechanism of both disease and recovery in order to determine the best possible modality and location of NSC administration. For example, in an experiment in which umbilical cord blood was administered either intravenously or intraparenchymally in rodents who had suffered a stroke, the recipients of the IV injections showed longer lasting recovery than those who receive intral-esional injections.63 The authors suggested that the cord blood cells aided in recovery by not only replacing lost cells, but also by inhibiting inflammation at the injury site.64 The transplanted cells were observed to not only migrate to the site of brain infarction, but also to the spleen where they altered the spleen function.65 These results offer important implications for diseases which involve extensive neurological damage within the CNS as well as a strong interaction with the peripheral immune system which may mitigate brain damage and aid in recovery. Therefore, to best treat a neurological or congenital metabolic disorder, one must fully understand the mechanism by which the disease attacks to best choose a route of administration.
In focal CNS disorders, such as Parkinson's disease or spinal cord injuries (SCI), intralesional administration of NSCs are perhaps best suited to treat local cell deficiencies. ES-cell-derived neuronal precursors have been shown to induce dopaminergic neuron differentiation in the substantia nigra to treat parkinsonism in rodent model brains.66,67 In SCI or experimental ischemic rodent models, intralesionally-transplanted aNSCs integrated with host tissue, differentiated preferentially into glial cells, released neurotrophic growth factors (i.e., BDNF, glial-derived neurotrophic factor (GDNF) and nerve growth factor (NGF)) and facilitated neurogenesis while inhibiting astrocytosis (the abnormal destruction of nearby neurons, generally caused by hypoglycemia or oxygen deprivation). Overall motor recovery was observed.17,68-70 In another experiment involving chemically demyelinated rat spinal cords, ES cells not only integrated and differentiated within the lesion, but in fact were found to have migrated up to 8 mm away from the lesion border, differentiating into astrocytes, oligodendrocytes and neurons.50,71,72 Introduction of stem cells directly into the brain parenchyma is most therapeutically applicable in cases of local brain insults; however, heterotopic migration or dispersal could lower therapeutic efficacy.
On the other hand, multifocal CNS disorders, such as amyotrophic lateral sclerosis (ALS), MS, or Alzheimer's disease are characterized by global inflammation and demyelination throughout the entire nervous system and are thus perhaps best treated by delivering NSCs intravenously or directly into the cerebrospinal fluid circulation to better facilitate distal cell delivery.8 NSCs travel universally throughout the vascular system and reach multiple inflamed areas in the brain and spinal cord by specific homing in on target cues. Evidence suggests that aNSCs express a variety of inflammatory molecules such as adhesion molecules, chemokines, cytokines and chemokine receptors8,73 which organize the migration and differentiation of precursors during development.73-75 These molecular signals support aNSC interactions with endothelial and ependymal cells surrounding inflamed brain tissues74,76,77 and create a chemoat-traction gradient78,79 that is cited as the main mechanism through which NSCs target inflamed areas of the CNS. In an EAE model (a murine model for human brain inflammation and MS), aNSC intravenous administration resulted in the functional recovery of myelin sheaths throughout the model through the selective homing to inflamed brain and spinal cord regions via membrane expression of CD44 and (VLA)-4.8 These two molecules played a vital role in the specific homing capabilities of encephalitogenic lymphocytes in EAE; therefore, Pluchino's results suggest that aNSCs might follow a similar molecular signal pathway in order to migrate to inflamed areas.8
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