title: Optic vesicle-like structures derived from human pluripotent stem cells facilitate a customized approach to retinal disease treatment.
abstract: Differentiation methods for human induced pluripotent stem cells (hiPSCs) typically yield progeny from multiple tissue lineages, limiting their use for drug testing and autologous cell transplantation. In particular, early retina and forebrain derivatives often intermingle in pluripotent stem cell cultures, owing to their shared ancestry and tightly coupled development. Here, we demonstrate that three-dimensional populations of retinal progenitor cells (RPCs) can be isolated from early forebrain populations in both human embryonic stem cell and hiPSC cultures, providing a valuable tool for developmental, functional, and translational studies. Using our established protocol, we identified a transient population of optic vesicle (OV)-like structures that arose during a time period appropriate for normal human retinogenesis. These structures were independently cultured and analyzed to confirm their multipotent RPC status and capacity to produce physiologically responsive retinal cell types, including photoreceptors and retinal pigment epithelium (RPE). We then applied this method to hiPSCs derived from a patient with gyrate atrophy, a retinal degenerative disease affecting the RPE. RPE generated from these hiPSCs exhibited a disease-specific functional defect that could be corrected either by pharmacological means or following targeted gene repair. The production of OV-like populations from human pluripotent stem cells should facilitate the study of human retinal development and disease and advance the use of hiPSCs in personalized medicine.
authors.affiliation: Waisman Center, University of Wisconsin, Madison, Wisconsin, USA. meyerjas@iupui.edu
authors.forename: Jason S
authors.initials: JS
authors.lastname: Meyer
authors.forename: Sara E
authors.initials: SE
authors.lastname: Howden
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Wallace
authors.forename: Amelia D
authors.initials: AD
authors.lastname: Verhoeven
authors.forename: Lynda S
authors.initials: LS
authors.lastname: Wright
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Capowski
authors.forename: Isabel
authors.initials: I
authors.lastname: Pinilla
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Martin
authors.forename: Shulan
authors.initials: S
authors.lastname: Tian
authors.forename: Ron
authors.initials: R
authors.lastname: Stewart
authors.forename: Bikash
authors.initials: B
authors.lastname: Pattnaik
authors.forename: James A
authors.initials: JA
authors.lastname: Thomson
authors.forename: David M
authors.initials: DM
authors.lastname: Gamm
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D015870:Gene Expression; D015316:Genetic Therapy; D015799:Gyrate Atrophy / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials; D018408:Patch-Clamp Techniques; D010786:Photoreceptor Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D039904:Pluripotent Stem Cells / Q000502:physiology*; D057285:Precision Medicine; D016548:Prosencephalon / Q000196:embryology; D012160:Retina / Q000196:embryology / Q000473:pathology; D012164:Retinal Diseases / Q000628:therapy*; D055213:Retinal Pigment Epithelium / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D014157:Transcription Factors; D000099176:Noggin Protein; C501126:DKK1 protein, human