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Summary Stem cell therapy has great prospects for brain white matter disorders, including the genetically determined disorders called leukodystrophies. We focus on the devastating leukodystrophy vanishing white matter (VWM). Patients with VWM show severe disability and early death, and treatment options are lacking. Previous studies showed successful cell replacement therapy in rodent models for myelin defects. However, proof-of-concept studies of allogeneic cell replacement in models representative of human leukodystrophies are lacking. We tested cell replacement in a mouse model representative of VWM. We transplanted different murine glial progenitor cell populations and showed improved pathological hallmarks and motor function. Improved mice showed a higher percentage of transplanted cells that differentiated into GFAP+ astrocytes, suggesting best therapeutic prospects for replacement of astroglial lineage cells. This is a proof-of-concept study for cell transplantation in VWM and suggests that glial cell replacement therapy is a promising therapeutic strategy for leukodystrophy patients., Graphical Abstract, Highlights • Cell therapy improved pathology and motor skills in vanishing white matter mice • Astrocyte differentiation of donor cells was associated with recovery of VWM symptoms, Vanishing white matter (VWM) is a severe genetic white matter disorder for which no curative treatment is available. Heine and colleagues show that transplantation with glial progenitor cells can improve pathology and motor skills in VWM mice. Improvement was correlated with increased astrocyte differentiation of donor cells, showing that astrocyte targeting is essential for VWM therapy.