14800-DvRappard

98 Chapter 6 DISCUSSION In brain tissue of MLD patients, HCT leads to presence of metabolically competent macrophages, able to digest sulfatides, as expected. There was clear macrophage activation in transplanted patients, notably with a polarization of these macrophages towards anM2-like phenotype. Oligodendrocyte precursors andmaturemyelin-forming oligodendrocytes were present in higher numbers in brain tissue of transplanted than untreated patients, suggesting an explanation for the improvement of MRI white matter changes in effective treatment. 4,5 Theobvious limitationof our study is that transplantation in the twoHCT-treatedpatients was not sufficient to halt disease progression. Evidently, brain tissue of successfully treated MLD patients cannot be obtained. Nonetheless, we found key differences between treated and untreated patients that help explain the improvement of MRI WM abnormalities in successfully treated patients. In theWM, M1-like macrophages are considered detrimental whereas M2-like cells support regeneration. The potential of M2-likemacrophages to sustain oligodendrocyte survival and remyelinationwas proven in vitro. Following demyelination, activated microglia signal to OPCs inducing them to proliferate and mature into myelin-forming cells. 17 M1-like macrophages dominate early after myelin loss and promote OPC proliferation. A switch to a M2-dominant phenotype is then necessary to bring about timely OPC differentiation. Consistent with this, M2-like macrophages predominate over M1-like cells in active multiple sclerosis lesions ongoing remyelination. 18 The findings of higher (mature) oligodendrocyte numbers in the WM of HCT-treated MLD patients suggests that HCT supports such M1-to-M2 switch resulting in a macrophage population that supports OPC survival and differentiation. In addition, ongoing myelin loss with abundance of myelin debris is a potent inhibitor of oligodendrocyte progenitor proliferation and maturation. 19 This myelin loss is moderated by metabolically competent macrophages. Both mechanisms are prerequisites for remyelination. Interestingly, in a Plp1 -overexpressing mouse model for Pelizaeus-Merzbacher disease, the prototype hypomyelinating leukodystrophy, 20 transplantation of neural and oligodendrocyte progenitor cells is also able to modify CNS inflammation by microglia polarization towards an M2-like phenotype, resulting in remyelination and prolonged survival. 21 This indicates that, besides myelin restoration, modulation of inflammation may be necessary to promote clinical recovery. Therapeutic strategies for MLD (and other lysosomal disorders) are changing: non- cellular options as enzyme replacement therapy and substrate inhibitors are being explored 22 and gene therapy by autologous genetically manipulated HCT has been shown effective. 7,23 Likely, MLD treatment in the future will be multimodal. Our data