title: Treatment of Inherited Eye Defects by Systemic Hematopoietic Stem Cell Transplantation.
abstract: OBJECTIVE
  Cystinosis is caused by a deficiency in the lysosomal cystine transporter, cystinosin (CTNS gene), resulting in cystine crystal accumulation in tissues. In eyes, crystals accumulate in the cornea causing photophobia and eventually blindness. Hematopoietic stem progenitor cells (HSPCs) rescue the kidney in a mouse model of cystinosis. We investigated the potential for HSPC transplantation to treat corneal defects in cystinosis.
  
  
  METHODS
  We isolated HSPCs from transgenic DsRed mice and systemically transplanted irradiated Ctns-/- mice. A year posttransplantation, we investigated the fate and function of HSPCs by in vivo confocal and fluorescence microscopy (IVCM), quantitative RT-PCR (RT-qPCR), mass spectrometry, histology, and by measuring the IOP. To determine the mechanism by which HSPCs may rescue disease cells, we transplanted Ctns-/- mice with Ctns-/- DsRed HSPCs virally transduced to express functional CTNS-eGFP fusion protein.
  
  
  RESULTS
  We found that a single systemic transplantation of wild-type HSPCs prevented ocular pathology in the Ctns-/- mice. Engraftment-derived HSPCs were detected within the cornea, and also in the sclera, ciliary body, retina, choroid, and lens. Transplantation of HSPC led to substantial decreases in corneal cystine crystals, restoration of normal corneal thickness, and lowered IOP in mice with high levels of donor-derived cell engraftment. Finally, we found that HSPC-derived progeny differentiated into macrophages, which displayed tunneling nanotubes capable of transferring cystinosin-bearing lysosomes to diseased cells.
  
  
  CONCLUSIONS
  To our knowledge, this is the first demonstration that HSPCs can rescue hereditary corneal defects, and supports a new potential therapeutic strategy for treating ocular pathologies.
authors.affiliation: Department of Pediatrics Division of Genetics, University of California, San Diego, La Jolla, California, United States.
authors.forename: Celine J
authors.initials: CJ
authors.lastname: Rocca
authors.affiliation: Shiley Eye Center, University of California, San Diego, California, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kreymerman
authors.affiliation: Department of Pediatrics Division of Genetics, University of California, San Diego, La Jolla, California, United States.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Ur
authors.affiliation: Department of Pathology, University of California, San Diego, California, United States.
authors.forename: Katie E
authors.initials: KE
authors.lastname: Frizzi
authors.affiliation: Department of Pediatrics Division of Genetics, University of California, San Diego, La Jolla, California, United States.
authors.forename: Swati
authors.initials: S
authors.lastname: Naphade
authors.affiliation: Department of Pediatrics Division of Genetics, University of California, San Diego, La Jolla, California, United States.
authors.forename: Athena
authors.initials: A
authors.lastname: Lau
authors.affiliation: Shiley Eye Center, University of California, San Diego, California, United States.
authors.forename: Tammy
authors.initials: T
authors.lastname: Tran
authors.affiliation: Department of Pathology, University of California, San Diego, California, United States.
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Calcutt
authors.affiliation: Shiley Eye Center, University of California, San Diego, California, United States 4Byers Eye Institute, Stanford University, Palo Alto, California, United States.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Goldberg
authors.affiliation: Department of Pediatrics Division of Genetics, University of California, San Diego, La Jolla, California, United States.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Cherqui
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003554:Cystinosis / Q000235:genetics / Q000628:therapy*; D004195:Disease Models, Animal; D005128:Eye Diseases / Q000151:congenital / Q000235:genetics / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic