TABLE 1.

Events that result in brain repair with allogeneic hematopoietic stem cell transplantation in Inborn Errors of Metabolism with neurological involvement.

1. Brain-conditioning: Busulfan-based conditioning regimen leads to depletion of malfunctioning host microglia, creating a permissive niche inside the brain microenvironment.

2. Brain engraftment: HSC and myeloid progenitors cross the BBB and occupy the microglial vacant niche, where they differentiate into microglia/macrophage.

3. Restored microglial function: donor-derived microglia/macrophages recapitulate native microglia function resulting in: • Improved scavenging and immune surveillance • Improved myelin debris clearance • Increased pro-regenerative M2 phenotype microglia • Differentiation of oligodendrocytes precursors into myelin-producing cells • Oligodendrocyte survival and proliferation signaling • BBB dysfunction correction

4. Cross-correction: donor-derived microglia/macrophages secrete functional enzyme to the extracellular matrix, which is then captured by neighboring oligodendrocytes and astrocytes through paracrine 6MP pathways.

HSC, hematopoietic stem cells; BBB, blood-brain barrier; 6MP, 6-mannose-phosphate.