14800-DvRappard

90 Chapter 6 ABSTRACT In metachromatic leukodystrophy (MLD), a lysosomal storage disorder, 1 hematopoietic cell transplantation (HCT), when performed early, stops brain demyelination and even allows remyelination, thereby halting white matter degeneration. 2-5 However, it remains unknown how disease stabilization is achieved. Brain tissue of eight patients with MLD, obtained at autopsy, was investigated for macrophage activation and polarization, myelin content and numbers of oligodendrocytes and their precursors. Additionally, sulfatide storage and digestion were assessed. Two of the patients had received HCT 10 to 12 months before death. We show that in brain tissue of transplanted MLD patients, metabolically competent donor macrophages are present and distributed throughout the white matter. Compared to untreated patients, these macrophages are activated and preferentially express markers of an M2 phenotype that supports oligodendrocyte survival and differentiation. The numbers of oligodendrocyte precursors and, even more, mature oligodendrocytes are increased in transplanted patients. Beyond cross- correction of enzyme deficiency, transplanted activated macrophages may play a neuroprotective role for resident oligodendrocytes, thereby enabling remyelination. Theseresults support the importanceofmodulationof inflammationforoligodendrocyte survival and myelin restoration in MLD, which could be exploited for better therapeutic outcome.