Transplantation of human umbilical mesenchymal stem cells cures the corneal defects of mucopolysaccharidosis VII mice

Authors


  • Author contributions: V.J.C.-T.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, and final approval of the manuscript; B.C.: supplied reagents and final approval of the manuscript; W.W.-Y.K.: conception and design, data analysis and interpretation, and final approval of the manuscript.

Correspondence: Vivien Jane Coulson-Thomas, Ph.D., Department of Ophthalmology, University of Cincinnati, CARE/Crawley Building, RM 5860, 3230 Eden Avenue, Cincinnati, Ohio 45267-0838, USA. Telephone: +1 513 658 5939; e-mail: vcoulsonthomas@gmail.com or vivien.coulson-thomas@uca.edu; or Winston Kao, Ph.D., Department of Ophthalmology, University of Cincinnati, CARE/Crawley Building, RM 5860, 3230 Eden Avenue, Cincinnati, Ohio 45267-0838, USA. Telephone: + 1 513 558 2802; e-mail: kaoww@ucmail.uc.edu

Abstract

Mucopolysaccharidosis (MPS) are a family of related disorders caused by a mutation in one of the lysosomal exoglycosidases which leads to the accumulation of glycosaminoglycans (GAGs). MPS VII, caused by a mutation in β-glucuronidase, manifests hepatomegaly, skeletal dysplasia, short stature, corneal clouding, and developmental delay. Current treatment regimens for MPS are not effective for treating corneal clouding and impaired mental development. We hypothesized that human umbilical mesenchymal stem cells (UMSCs) transplanted into the corneal stroma could participate in the catabolism of GAGs providing a means of cell therapy for MPS. For such treatment, human UMSCs were intrastromally transplanted into corneas of MPS VII mice. UMSC transplantation restored the dendritic and hexagonal morphology of host keratocytes and endothelial cells, respectively, and in vivo confocal microscopy (HRT-II) revealed reduced corneal haze. Immunohistochemistry using antibodies against heparan sulfate and chondroitin sulfate chains as well as lysosomal-associated membrane protein 2 revealed a decrease in GAG content and both lysosomal number and size in the treated corneas. Labeling UMSC intracellular compartments prior to transplantation revealed the distribution of UMSC vesicles throughout the corneal stroma and endothelium. An in vitro coculture assay between skin fibroblasts isolated from MPS VII mice and UMSC demonstrated that neutral vesicles released by the UMSC are taken up by the fibroblasts and proceed to fuse with the acidic lysosomes. Therefore, transplanted UMSCs participate both in extracellular GAG turnover and enable host keratocytes to catabolize accumulated GAG products, suggesting that UMSC could be a novel alternative for treating corneal defects associated with MPS and other congenital metabolic disorders. Stem Cells 2013;31:2116–2126

Ancillary