Stem cell microvesicles transfer cystinosin to human cystinotic cells and reduce cystine accumulation in vitro

Diana M. Iglesias, Reyhan El-Kares, Anna Taranta, Francesco Bellomo, Francesco Emma, Martine Besouw, Elena Levtchenko, Jaan Toelen, Lambertus van den Heuvel, LeeLee Chu, Jing Zhao, Yoon Kow Young, Nicoletta Eliopoulos, Paul Goodyer

Research output: Contribution to journalArticle

Abstract

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 CTNSRed 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.

Original languageEnglish
Article numbere42840
JournalPLoS One
Volume7
Issue number8
DOIs
Publication statusPublished - Aug 13 2012

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Iglesias, D. M., El-Kares, R., Taranta, A., Bellomo, F., Emma, F., Besouw, M., Levtchenko, E., Toelen, J., van den Heuvel, L., Chu, L., Zhao, J., Young, Y. K., Eliopoulos, N., & Goodyer, P. (2012). Stem cell microvesicles transfer cystinosin to human cystinotic cells and reduce cystine accumulation in vitro. PLoS One, 7(8), [e42840]. https://doi.org/10.1371/journal.pone.0042840