title: Transplantation of human umbilical mesenchymal stem cells cures the corneal defects of mucopolysaccharidosis VII mice.
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.
authors.affiliation: Department of Ophthalmology, College of Medicine, Edith J. Crawley Vision Research Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Vivien Jane
authors.initials: VJ
authors.lastname: Coulson-Thomas
authors.forename: Bruce
authors.initials: B
authors.lastname: Caterson
authors.forename: Winston W-Y
authors.initials: WW
authors.lastname: Kao
mesh_terms: D000818:Animals; D018920:Coculture Techniques; D003316:Corneal Diseases / Q000628:therapy*; D060527:Corneal Keratocytes / Q000378:metabolism; D003319:Corneal Stroma / Q000378:metabolism / Q000473:pathology; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016538:Mucopolysaccharidosis VII / Q000628:therapy*; D010590:Phalloidine / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D006025:Glycosaminoglycans; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D010590:Phalloidine
keywords: Cornea; Exosomes; Glycosaminoglycans; Mucopolysaccharidosis; Umbilical cord mesenchymal stem cells
references.citation: Hum Mutat. 2009 Apr;30(4):511-9
references.pmid: 19224584
references.citation: Proc Natl Acad Sci U S A. 1973 Feb;70(2):320-4
references.pmid: 4119786
references.citation: Am J Pathol. 1990 Jan;136(1):207-17
references.pmid: 2105058
references.citation: Proc Natl Acad Sci U S A. 1990 Mar;87(5):1913-6
references.pmid: 2308952
references.citation: PLoS One. 2010 May 19;5(5):e10707
references.pmid: 20502663
references.citation: IUBMB Life. 2010 Jan;62(1):33-40
references.pmid: 20014233
references.citation: Hum Mol Genet. 2008 Mar 15;17(6):815-24
references.pmid: 18056156
references.citation: J Biol Chem. 2001 Nov 16;276(46):43160-5
references.pmid: 11562370
references.citation: Mol Genet Metab. 2012 Sep;107(1-2):161-72
references.pmid: 22902520
references.citation: Hum Genet. 1997 Dec;101(3):355-8
references.pmid: 9439667
references.citation: Biochem Soc Trans. 2010 Dec;38(6):1465-8
references.pmid: 21118108
references.citation: Drugs. 2007;67(18):2697-716
references.pmid: 18062719
references.citation: J Inherit Metab Dis. 1998 Aug;21(5):575-86
references.pmid: 9728337
references.citation: Adv Genet. 2001;44:165-71
references.pmid: 11596981
references.citation: Birth Defects Orig Artic Ser. 1976;12(3):133-53
references.pmid: 821556
references.citation: J Cell Mol Med. 2012 May;16(5):1114-24
references.pmid: 21883890
references.citation: Pediatr Res. 1996 Jun;39(6):1050-4
references.pmid: 8725268
references.citation: Int J Proteomics. 2012;2012:971907
references.pmid: 22852084
references.citation: J Cell Physiol. 2007 Apr;211(1):27-35
references.pmid: 17226788
references.citation: Eur Rev Med Pharmacol Sci. 2011 Mar;15(3):253-8
references.pmid: 21528770
references.citation: Curr Eye Res. 2000 Apr;20(4):260-7
references.pmid: 10806439
references.citation: J Clin Invest. 1994 Jun;93(6):2324-31
references.pmid: 8200966
references.citation: Birth Defects Orig Artic Ser. 1974;10(12):239-45
references.pmid: 4282258
references.citation: Biochem Biophys Res Commun. 2007 Mar 16;354(3):700-6
references.pmid: 17257581
references.citation: Hum Genet. 1976 Jun 29;32(3):233-55
references.pmid: 820626
references.citation: Ann Neurol. 2004 Apr;55(4):495-502
references.pmid: 15048888
references.citation: Mol Ther. 2006 Dec;14(6):840-50
references.pmid: 16965940
references.citation: J Neurol Neurosurg Psychiatry. 1987 Jun;50(6):699-703
references.pmid: 3112309
references.citation: Ann N Y Acad Sci. 1971 Jul 6;179:580-7
references.pmid: 4255108
references.citation: J Inherit Metab Dis. 2008 Aug;31(4):473-80
references.pmid: 18618289
references.citation: J Biol Chem. 2005 Jul 8;280(27):25541-7
references.pmid: 15849191
references.citation: J Cell Sci. 2002 Dec 1;115(Pt 23):4517-31
references.pmid: 12414997
references.citation: Glycoconj J. 2002 May-Jun;19(4-5):275-85
references.pmid: 12975606
references.citation: J Clin Lab Anal. 2010;24(3):149-53
references.pmid: 20486194
references.citation: Stem Cells. 2008 Sep;26(9):2287-99
references.pmid: 18566331
references.citation: Helv Paediatr Acta. 1978 Nov;33(4-5):413-28
references.pmid: 101485
references.citation: Curr Opin Cell Biol. 2008 Oct;20(5):495-501
references.pmid: 18640274
references.citation: Expert Rev Mol Med. 2008 Jan 18;10:e1
references.pmid: 18201392