Intrinsic resistance of neural stem cells to toxic metabolites may make them well suited for cell non‐autonomous disorders: evidence from a mouse model of Krabbe leukodystrophy

Abstract

While transplanted neural stem cells (NSCs) have been shown to hold promise for cell replacement in models of a number of neurological disorders, these examples have typically been under conditions where the host cells become dysfunctional due to a cell autonomous etiology, i.e. a 'sick' cell within a relatively supportive environment. It has long been held that cell replacement in a toxic milieu would not likely be possible; donor cells would succumb in much the same way as endogenous cells had. Many metabolic diseases are characterized by this situation, suggesting that they would be poor targets for cell replacement therapies. On the other hand, models of such diseases could prove ideal for testing the capacity for cell replacement under such challenging conditions. In the twitcher (twi) mouse-as in patients with Krabbe or globoid cell leukodystrophy (GLD), for which it serves as an authentic model-loss of galactocerebrosidase (GalC) activity results in the accumulation of psychosine, a toxic glycolipid. Twi mice, like children with GLD, exhibit inexorable neurological deterioration presumably as a result of dysfunctional and ultimately degenerated oligodendrocytes with loss of myelin. It is believed that GLD pathophysiology is related to a psychosine-filled environment that kills not only host oligodendrocytes but theoretically any new cells placed into that milieu. Through the implantation of NSCs into the brains of both neonatal and juvenile/young adult twi mice, we have determined that widespread oligodendrocyte replacement and remyelination is feasible. NSCs appear to be intrinsically resistant to psychosine-more so in their undif-ferentiated state than when directed ex vivo to become oligodendrocytes. This resistance can be enhanced by engineering the NSCs to over-express GalC. Some twi mice grafted with such engineered NSCs had thicker white tracts and lived 2-3 times longer than expected. While their brains had detectable levels of GalC, it was probably more significant that their psychosine levels were lower than in twi mice that

Combined transplantation of neural precursor cells and olfactory ensheathing cells for the treatment of X-linked adrenoleukodystrophy in children

“…23,24 The results suggest that NPC could attenuate damage to motor functions. Transplanted mouse NPC or gene-modified NPC (overexpressed β-galactocerebrosidase [GALC]) could survive for a long time in the brain of a globoid cell leukodystrophy mouse model, produce functional GALC and enhance the enzyme activity in the brain and spinal cord, reduce accumulation of galactocerebroside, delay symptom onset, and extend their life spans to 2-3 times longer than expected.…”

“…24 No transplantation-related severe adverse events occurred during the study. Shihabuddin et al 22 found that many sites within the brain transplantation of adult mouse NPC with the overexpressed acid sphingomyelinase gene (ASM) into the Niemann-Pick-A mouse (ASM gene knocked out) led to a marked regional decrease in free cholesterol and sphingomyelin storage.…”

“…In addition, these transplanted NPC had a substitution effect on oligodendrocytes and a remyelination effect. 24,25 All these studies demonstrated that NPC had the abilities of migration, regional-specific differentiation, removing various accumulations in the brain and reducing damage to motor functions, suggesting the potential of NPC in the clinical treatment of ALD and the possibility of its restorative effect at some level.…”

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

“…This would seem to match the likely scenario well in treating children with leukodystrophies. However, transplantation of OPCs has also been carried out in adult shi mice [78][79][80] and in the sh pup [52] with successful myelination. This is not always true in all of the myelin mutants, as we and others have had little success in transplanting OPCs into the CNS of the taiep rat.…”

“…6). In 1 study, a neural stem cell line genetically modified to overproduce GALC was transplanted into the twi brain [78]. The donor cells appeared to have migrated, proliferated, and finally distributed widely in the brain, although the proportion of donor cells that differentiated into myelinating OLs is unclear.…”