Stem cell microvesicles transfer cystinosin to human cystinotic cells and reduce cystine accumulation in vitro.
Cystinosis is a rare disease caused by homozygous mutations of the CTNS gene, encoding a cystine efflux channel in the lysosomal membrane. In Ctns knockout mice, the pathologic intralysosomal accumulation of cystine that drives progressive organ damage can be reversed by infusion of wildtype bone marrow-derived stem cells, but the mechanism involved is unclear since the exogeneous stem cells are rarely integrated into renal tubules. Here we show that human mesenchymal stem cells, from amniotic fluid or bone marrow, reduce pathologic cystine accumulation in co-cultured CTNS mutant fibroblasts or proximal tubular cells from cystinosis patients. This paracrine effect is associated with release into the culture medium of stem cell microvesicles (100-400 nm diameter) containing wildtype cystinosin protein and CTNS mRNA. Isolated stem cell microvesicles reduce target cell cystine accumulation in a dose-dependent, Annexin V-sensitive manner. Microvesicles from stem cells expressing CTNS(Red) transfer tagged CTNS protein to the lysosome/endosome compartment of cystinotic fibroblasts. Our observations suggest that exogenous stem cells may reprogram the biology of mutant tissues by direct microvesicle transfer of membrane-associated wildtype molecules.
Department of Pediatrics, Montreal Children's Hospital Research Institute, McGill University, Montréal, Québec, Canada.
Diana M
DM
Iglesias
Reyhan
R
El-Kares
Anna
A
Taranta
Francesco
F
Bellomo
Francesco
F
Emma
Martine
M
Besouw
Elena
E
Levtchenko
Jaan
J
Toelen
Lambertus
L
van den Heuvel
Leelee
L
Chu
Jing
J
Zhao
Yoon Kow
YK
Young
Nicoletta
N
Eliopoulos
Paul
P
Goodyer
D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003553:Cystine / Q000378:metabolism*; D003554:Cystinosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D055354:Exosomes / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D009154:Mutation; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D026921:Amino Acid Transport Systems, Neutral; C111445:CTNS protein, human; D012333:RNA, Messenger; D003553:Cystine