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Patient-specific induced pluripotent stem cell-derived RPE cells: Understanding the pathogenesis of retinopathy in long-chain 3-hydroxyacyl-CoA dehydrogenase deiciency
Research Program of Molecular Neurology, Biomedicum 1, University of Helsinki, Helsinki, Finland.
Institute of Biomedical Technology, University of Tampere, Tampere, Finland; BioMediTech, Tampere, Finland.
Research Program of Molecular Neurology, Biomedicum 1, University of Helsinki, Helsinki, Finland.
Valtion Teknillinen Tutkimuskeskus (VTT) Technical Research Centre of Finland, Espoo, Finland.
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2015 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 56, no 5, p. 3371-3382Article in journal (Refereed) Published
Abstract [en]

Purpose: Retinopathy is an important manifestation of trifunctional protein (TFP) deficiencies but not of other defects of fatty acid oxidation. The common homozygous mutation in the TFP α-subunit gene HADHA (hydroxyacyl-CoA dehydrogenase), c.1528G>C, affects the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity of TFP and blindness in infancy. The pathogenesis of the retinopathy is unknown. This study aimed to utilize human induced pluripotent stem cell (hiPSC) technology to create a disease model for the disorder, and to derive clues for retinopathy pathogenesis.

Methods: We implemented hiPSC technology to generate LCHAD deficiency (LCHADD) patient-specific retinal pigment epithelial (RPE) monolayers. These patient and control RPEs were extensively characterized for function and structure, as well as for lipid composition by mass spectrometry.

Results: The hiPSC-derived RPE monolayers of patients and controls were functional, as they both were able to phagocytose the photoreceptor outer segments in vitro. Interestingly, the patient RPEs had intense cytoplasmic neutral lipid accumulation, and lipidomic analysis revealed an increased triglyceride accumulation. Further, patient RPEs were small and irregular in shape, and their tight junctions were disorganized. Their ultrastructure showed decreased pigmentation, few melanosomes, and more melanolysosomes.

Conclusions: We demonstrate that the RPE cell model reveals novel early pathogenic changes in LCHADD retinopathy, with robust lipid accumulation, inefficient pigmentation that is evident soon after differentiation, and a defect in forming tight junctions inducing apoptosis. We propose that LCHADD-RPEs are an important model for mitochondrial TFP retinopathy, and that their early pathogenic changes contribute to infantile blindness of LCHADD.

Place, publisher, year, edition, pages
Lippincott-Raven Publishers , 2015. Vol. 56, no 5, p. 3371-3382
Keywords [en]
Retinopathy, mitochondria, beta oxidation, retinal pigment epithelium
National Category
Medical and Health Sciences Ophthalmology
Identifiers
URN: urn:nbn:se:oru:diva-65679DOI: 10.1167/iovs.14-14007ISI: 000356439200075PubMedID: 26024122Scopus ID: 2-s2.0-84939639353OAI: oai:DiVA.org:oru-65679DiVA, id: diva2:1189781
Funder
Academy of Finland, 130497, 218050EU, European Research Council
Note

Cited By :10; Export Date: 12 March 2018; Article

Funding Agencies:

Jane and Aatos Erkko Foundation, Helsinki, Finland

Pediatric Research Foundation, Helsinki, Finland

Mary and Georg Ehrnooth Foundation, Helsinki, Finland

Sigrid Juselius Foundation

Available from: 2018-03-12 Created: 2018-03-12 Last updated: 2018-07-09Bibliographically approved

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Hyötyläinen, Tuulia

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