Open AccessBrief Reports: Lysosomal Cross‐Correction by Hematopoietic Stem Cell‐Derived Macrophages Via Tunneling Nanotubes
Author(s) -
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
Publication year - 2015
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.1835
Subject(s) - cystinosis , invadopodia , biology , microbiology and biotechnology , stem cell , lysosomal storage disease , haematopoiesis , transplantation , hematopoietic stem cell , cystine , biochemistry , genetics , cancer cell , medicine , surgery , cancer , cysteine , enzyme
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