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

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)....

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Published in:Stem cells (Dayton, Ohio) Ohio), 2015-01, Vol.33 (1), p.301-309
Main Authors: Naphade, Swati, Sharma, Jay, Gaide Chevronnay, Héloïse P., Shook, Michael A., Yeagy, Brian A., Rocca, Celine J., Ur, Sarah N., Lau, Athena J., Courtoy, Pierre J., Cherqui, Stephanie
Format: Article
Language:English
Subjects:
Animals
Cystinosis
Cystinosis - metabolism
Cystinosis - pathology
Cystinosis - therapy
Fibroblasts
Hematopoietic Stem Cell Transplantation
Hematopoietic stem cells
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Humans
Lysosomal cross‐correction
Lysosomes - metabolism
Macrophages
Macrophages - cytology
Macrophages - metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nanotubes
Stem cells
Tubular basement membrane
Tunneling nanotubes
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Summary: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. Stem Cells 2015;33:301–309
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.1835