title: Continuous non-cell autonomous reprogramming to generate retinal ganglion cells for glaucomatous neuropathy.
abstract: Glaucoma, where the retinal ganglion cells (RGCs) carrying the visual signals from the retina to the visual centers in the brain are progressively lost, is the most common cause of irreversible blindness. The management approaches, whether surgical, pharmacological, or neuroprotective do not reverse the degenerative changes. The stem cell approach to replace dead RGCs is a viable option but currently faces several barriers, such as the lack of a renewable, safe, and ethical source of RGCs that are functional and could establish contacts with bona fide targets. To address these barriers, we have derived RGCs from the easily accessible adult limbal cells, reprogrammed to pluripotency by a non-nucleic acid approach, thus circumventing the risk of insertional mutagenesis. The generation of RGCs from the induced pluripotent stem (iPS) cells, also accomplished non-cell autonomously, recapitulated the developmental mechanism, ensuring the predictability and stability of the acquired phenotype, comparable to that of native RGCs at biochemical, molecular, and functional levels. More importantly, the induced RGCs expressed axonal guidance molecules and demonstrated the potential to establish contacts with specific targets. Furthermore, when transplanted in the rat model of ocular hypertension, these cells incorporated into the host RGC layer and expressed RGC-specific markers. Transplantation of these cells in immune-deficient mice did not produce tumors. Together, our results posit retinal progenitors generated from non-nucleic acid-derived iPS cells as a safe and robust source of RGCs for replacing dead RGCs in glaucoma.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Parameswaran
authors.affiliation: Department of Pharmacology, Creighton University, Omaha, Nebraska, USA.
authors.forename: Shashank Manohar
authors.initials: SM
authors.lastname: Dravid
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Pooja
authors.initials: P
authors.lastname: Teotia
authors.affiliation: Department of Cell Biology and Anatomy, UNT Health Science Center, Fort Worth, Texas, USA.
authors.forename: Raghu R
authors.initials: RR
authors.lastname: Krishnamoorthy
authors.affiliation: Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Toris
authors.affiliation: The Kenneth C. Swan Ocular Neurobiology Laboratory, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: John
authors.initials: J
authors.lastname: Morrison
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Iqbal
authors.initials: I
authors.lastname: Ahmad
mesh_terms: D000818:Animals; D064987:Cell- and Tissue-Based Therapy; D065150:Cellular Reprogramming / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D005901:Glaucoma / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000637:transplantation; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009798:Ocular Hypertension / Q000473:pathology*; D010523:Peripheral Nervous System Diseases / Q000209:etiology*; D012165:Retinal Ganglion Cells / Q000166:cytology*
keywords: Glaucoma; Induced pluripotent stem cells; Non-cell autonomous; Retinal ganglion cells; Teratoma