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Human neural progenitor cells decrease photoreceptor degeneration, normalize opsin distribution and support synapse structure in cultured porcine retina
Örebro University, School of Health Sciences.
Department of Chemistry and Biomedicine, Linnaeus University, Kalmar, Sweden.
Örebro University, School of Health Sciences.
2016 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1646, 522-534 p.Article in journal (Refereed) Published
Abstract [en]

Retinal neurodegenerative disorders like retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy and retinal detachment decrease retinal functionality leading to visual impairment. The pathological events are characterized by photoreceptor degeneration, synaptic disassembly, remodeling of postsynaptic neurons and activation of glial cells. Despite intense research, no effective treatment has been found for these disorders. The current study explores the potential of human neural progenitor cell (hNPC) derived factors to slow the degenerative processes in adult porcine retinal explants. Retinas were cultured for 3 days with or without hNPCs as a feeder layer and investigated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), immunohistochemical, western blot and quantitative real time-polymerase chain reaction (qRT-PCR) techniques. TUNEL showed that hNPCs had the capacity to limit photoreceptor cell death. Among cone photoreceptors, hNPC coculture resulted in better maintenance of cone outer segments and reduced opsin mislocalization. Additionally, maintained synaptic structural integrity and preservation of second order calbindin positive horizontal cells was also observed. However, Müller cell gliosis only seemed to be alleviated in terms of reduced Müller cell density. Our observations indicate that at 3 days of coculture, hNPC derived factors had the capacity to protect photoreceptors, maintain synaptic integrity and support horizontal cell survival. Human neural progenitor cell applied treatment modalities may be an effective strategy to help maintain retinal functionality in neurodegenerative pathologies. Whether hNPCs can independently hinder Müller cell gliosis by utilizing higher concentrations or by combination with other pharmacological agents still needs to be determined.

Place, publisher, year, edition, pages
Amsterdam, Netherlands: Elsevier, 2016. Vol. 1646, 522-534 p.
Keyword [en]
Photoreceptor degeneration, synapse, opsin, gliosis, neuroprotection
National Category
Neurosciences Ophthalmology
Research subject
Neurology
Identifiers
URN: urn:nbn:se:oru:diva-51995DOI: 10.1016/j.brainres.2016.06.039ISI: 000381844700059PubMedID: 27369448Scopus ID: 2-s2.0-84978831975OAI: oai:DiVA.org:oru-51995DiVA: diva2:959326
Note

Funding Agencies:

Faculty of Natural Sciences at Linnaeus University

Faculty of Medical Sciences at Örebro University 

Olle Engkvist Foundation

Ögonfonden

Crown Princess Margaretas Committee for the Blind

Edwin Jordan Foundation

Available from: 2016-09-07 Created: 2016-09-06 Last updated: 2016-11-21Bibliographically approved
In thesis
1. Photoreceptor degeneration, second order neuron remodeling and glia reactivity in an in vivo and in vitro model of retinal neurodegeneration
Open this publication in new window or tab >>Photoreceptor degeneration, second order neuron remodeling and glia reactivity in an in vivo and in vitro model of retinal neurodegeneration
2016 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Photoreceptors have the ability to last during the entire lifespan of an individual. Being the first line of neurons in the visual transduction pathway, their health and maintenance is eminent for proper retinal function. However, photoreceptors are susceptible to neurodegenerative retinal dystrophies. A number of retinal pathologies such as retinitis pigmentosa, age-related amacular degeneration and diabetic retinopathy have been linked to photoreceptor death. Moreover, photoreceptor degeneration has been shown to affect downstream inner nuclear layer cells as well as induce reactive responses from Müller cells and microglia. Since current treatments are ineffective in preventing the degeneration of these neurons, intense research is still underway to discover novel treatment modalities. In this thesis, photoreceptor degeneration was assessed in an in vivo and in vitro model of neurodegeneration. Moreover, a possible mode of preserving these neurons by the use of human neural progenitor cells (hNPCs) was investigated. The in vivo pdgf-bret/ret (platelet derived growth factor-b retention motif knockout) mouse model, which shows severe vascular pathology as a result of detachment of pericytes from the vascular endothelium, was studied during the first postnatal month. In a short time span, i.e. between postnatal day (P)10 and P15, retinopathic features were observed. Photoreceptor degeneration related to cell death, cone outer segment (OS) shortening and synapse disassembly in the outer plexiform layer (OPL) was seen. The second order rod bipolar cells underwent remodeling and the Müller cells became gliotic with increased expression of GFAP (glial fibrillary acidic protein). Microglial cells were also observed to convert to their reactive amoeboid-like phenotype. These features seemed to become more severe in the older P28 mutants. In the in vitro porcine retinal explant model, photoreceptor death significantly increased by 3 days in vitro (div). This was associated with loss of cone OSs, opsin mislocalization and loss of synaptic integrity in the OPL. Horizontal cell death and remodeling was also observed together with a severe gliotic response from the Müller cells. Human neural progenitor cell cocultured explants for 3 div had the ability to preserve photoreceptor survival by means of OS conservation, better opsin trafficking and maintaining synaptic integrity. However, Müller cell gliosis was only mitigated by a decreased density of GFAP immunoreactive Müller cells. In conclusion, both the in vivo and in vitro model of neurodegeneration demonstrate the vulnerability of photoreceptors to various mechanisms of retinal injury. Interestingly, hNPC derived neurotrophic factors had neuroprotective qualities in 3 div porcine retinal explants.

Place, publisher, year, edition, pages
Örebro: Örebro University, 2016. 40 p.
National Category
Other Basic Medicine
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-53596 (URN)
Presentation
2016-11-23, Örebro universitet, Campus USÖ, Hörsal C1, Södra Grev Rosengatan 30, Örebro, 13:15 (Swedish)
Available from: 2016-11-21 Created: 2016-11-21 Last updated: 2016-11-21Bibliographically approved

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