Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 3371-3382 |
| Journal | Investigative Ophthalmology and Visual Science |
| Volume | 56 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2015 |
| MoE publication type | A1 Journal article-refereed |
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Keywords
- beta oxidation
- mitochondria
- retinal pigment epithelium
- retinopathy
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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. / Polinati, Padmini P.; Ilmarinen, Tanja; Trokovic, Ras; Hyotylainen, Tuulia; Otonkoski, Timo; Suomalainen, Anu; Skottman, Heli; Tyni, Tiina.
In: Investigative Ophthalmology and Visual Science, Vol. 56, No. 5, 2015, p. 3371-3382.Research output: Contribution to journal › Article › Scientific › peer-review
TY - JOUR
T1 - Patient-specific induced pluripotent stem cell-derived RPE cells
T2 - Understanding the pathogenesis of retinopathy in long-chain 3-hydroxyacyl-CoA dehydrogenase deiciency
AU - Polinati, Padmini P.
AU - Ilmarinen, Tanja
AU - Trokovic, Ras
AU - Hyotylainen, Tuulia
AU - Otonkoski, Timo
AU - Suomalainen, Anu
AU - Skottman, Heli
AU - Tyni, Tiina
PY - 2015
Y1 - 2015
N2 - 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 a-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 ultratructure 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.
AB - 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 a-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 ultratructure 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.
KW - beta oxidation
KW - mitochondria
KW - retinal pigment epithelium
KW - retinopathy
U2 - 10.1167/iovs.14-14007
DO - 10.1167/iovs.14-14007
M3 - Article
VL - 56
SP - 3371
EP - 3382
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
SN - 0146-0404
IS - 5
ER -