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Despite controversies on the potential of hematopoietic stem cells (HSCs) to promote tissue repair, we previously showed that HSC transplantation could correct cystinosis, a multisystemic lysosomal storage disease, caused by a defective lysosomal membrane cystine transporter, cystinosin ( CTNS  gene). Addressing the cellular mechanisms, we here report vesicular cross‐correction after HSC differentiation into macrophages. Upon coculture with cystinotic fibroblasts, macrophages produced tunneling nanotubes (TNTs) allowing transfer of cystinosin‐bearing lysosomes into Ctns‐deficient cells, which exploited the same route to retrogradely transfer cystine‐loaded lysosomes to macrophages, providing a bidirectional correction mechanism. TNT formation was enhanced by contact with diseased cells. In vivo, HSCs grafted to cystinotic kidneys also generated nanotubular extensions resembling invadopodia that crossed the dense basement membranes and delivered cystinosin into diseased proximal tubular cells. This is the first report of correction of a genetic lysosomal defect by bidirectional vesicular exchange via TNTs and suggests broader potential for HSC transplantation for other disorders due to defective vesicular proteins. S tem  C ells   2015;33:301–309

Brief Reports: Lysosomal Cross‐Correction by Hematopoietic Stem Cell‐Derived Macrophages Via Tunneling Nanotubes