Generation of patient-specific induced pluripotent stem cells from Leber's hereditary optic neuropathy

Lu, Huai En; Yang, Yi; Chen, Yan Ting; Wu, You Ren; Wang, Chia Lin; Tsai, Fu Ting; Hwang, De‐Kuang; Lin, Tzu‐Chin; Chen, Shih‐Jen; Wang, An Guor; Hsieh, Patrick Chingo-Ho; Chiou, Shih Hwa

doi:10.1016/j.scr.2018.01.029

Cited by 15 publications

(7 citation statements)

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“…hiPSCs were generated from peripheral blood mononuclear cells obtained from a healthy control donor and LHON patient by overexpression of four reprogramming factors, Oct-4, SOX2, c-Myc and KLF4, based on our previously published protocol [18]. RGCs were then differentiated from the generated hiPSCs in a stepwise manner following the protocol adapted from Ohlemacher [19] with several modifications as outlined in Figure 2A.…”

Section: Resultsmentioning

confidence: 99%

“…Since RGCs appear at the early stage of retina development, it was suggested that RGCs could be isolated from the OVs at 25–30 days after the initiation of differentiation [22]. We have successfully differentiated hiPSCs derived from LHON patients and purified RGCs from the OVs [18,24]. Still, little is known about the pathogenic mechanisms of LHON.…”

Section: Discussionmentioning

confidence: 99%

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Glutamate Stimulation Dysregulates AMPA Receptors-Induced Signal Transduction Pathway in Leber’s Inherited Optic Neuropathy Patient-Specific hiPSC-Derived Retinal Ganglion Cells

Yang

Nguyen

Lin

et al. 2019

Cells

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The mitochondrial genetic disorder, Leber’s hereditary optic neuropathy (LHON), is caused by a mutation in MT-ND4 gene, encoding NADH dehydrogenase subunit 4. It leads to the progressive death of retinal ganglion cells (RGCs) and causes visual impairment or even blindness. However, the precise mechanisms of LHON disease penetrance and progression are not completely elucidated. Human-induced pluripotent stem cells (hiPSCs) offer unique opportunities to investigate disease-relevant phenotypes and regulatory mechanisms underlying LHON pathogenesis at the cellular level. In this study, we successfully generated RGCs by differentiation of LHON patient-specific hiPSCs. We modified the protocol of differentiation to obtain a more enriched population of single-cell RGCs for LHON study. Based on assessing morphology, expression of specific markers and electrophysiological activity, we found that LHON-specific hiPSC-derived were more defective in comparison with normal wild-type RGCs. Based on our previous study, whereby by using microarray analysis we identified that the components of glutamatergic synapse signaling pathway were significantly downregulated in LHON-specific RGCs, we focused our study on glutamate-associated α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. We found that the protein expression levels of the subunits of the AMPA receptor, GluR1 and GluR2, and their associated scaffold proteins were decreased in LHON-RGCs. By performing the co-immunoprecipitation assay, we found several differences in the efficiencies of interaction between AMPA subunits and scaffold proteins between normal and LHON-specific RGCs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Glutamate Stimulation Dysregulates AMPA Receptors-Induced Signal Transduction Pathway in Leber’s Inherited Optic Neuropathy Patient-Specific hiPSC-Derived Retinal Ganglion Cells

Yang

Nguyen

Lin

et al. 2019

Cells

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“…They observed a return of apoptosis to normal levels in the cybrid-corrected RGCs in comparison with the increased levels found in LHON iPSC-derived RGCs [102]. More groups generated iPSC models of LHON with the representative mutation m.11778G>C; p.Arg340His [103,104]. One of them, Wu et al, showed defective neurite outgrowth in RGCs differentiated from patient iPSCs and improved mitochondrial biogenesis as a compensatory mechanism.…”

Section: Potential Applications For Ipsc-derived Rgcsmentioning

confidence: 99%

Hereditary Optic Neuropathies: Induced Pluripotent Stem Cell-Based 2D/3D Approaches

García-López

Arenas

Gallardo

2021

Genes

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Inherited optic neuropathies share visual impairment due to the degeneration of retinal ganglion cells (RGCs) as the hallmark of the disease. This group of genetic disorders are caused by mutations in nuclear genes or in the mitochondrial DNA (mtDNA). An impaired mitochondrial function is the underlying mechanism of these diseases. Currently, optic neuropathies lack an effective treatment, and the implementation of induced pluripotent stem cell (iPSC) technology would entail a huge step forward. The generation of iPSC-derived RGCs would allow faithfully modeling these disorders, and these RGCs would represent an appealing platform for drug screening as well, paving the way for a proper therapy. Here, we review the ongoing two-dimensional (2D) and three-dimensional (3D) approaches based on iPSCs and their applications, taking into account the more innovative technologies, which include tissue engineering or microfluidics.

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“…Multiple iPSC lines have been generated from fibroblasts of LHON patients. These lines offer unique opportunities to investigate LHON phenotypes and regulatory mechanisms at the cellular level ( 59 – 61 ). Unfortunately, the generated cells are not organized as they would be in the retina, which prevents their use in cell therapy.…”

Section: Medical Treatmentmentioning

confidence: 99%

Leber Hereditary Optic Neuropathy: Review of Treatment and Management

Hage

Vignal-Clermont

2021

Front. Neurol.

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Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease that specifically targets the retinal ganglion cells by reducing their ability to produce enough energy to sustain. The mutations of the mitochondrial DNA that cause LHON are silent until an unknown trigger causes bilateral central visual scotoma. After the onset of loss of vision, most patients experience progressive worsening within the following months. Few of them regain some vision after a period of ~1 year. Management of LHON patients has been focused on understanding the triggers of the disease and its pathophysiology to prevent the onset of visual loss in a carrier. Medical treatment is recommended once visual loss has started in at least one eye. Research evaluated drugs that are thought to be able to restore the mitochondrial electron transport chain of the retinal ganglion cells. Significant advances were made in evaluating free radical cell scavengers and gene therapy as potential treatments for LHON. Although encouraging the results of clinical trial have been mixed in stopping the worsening of visual loss. In patients with chronic disease of over 1 year, efficient treatment that restores vision is yet to be discovered. In this review, we summarize the management strategies for patients with LHON before, during, and after the loss of vision, explain the rationale and effectiveness of previous and current treatments, and report findings about emerging treatments.

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Generation of patient-specific induced pluripotent stem cells from Leber's hereditary optic neuropathy

Cited by 15 publications

References 1 publication

Glutamate Stimulation Dysregulates AMPA Receptors-Induced Signal Transduction Pathway in Leber’s Inherited Optic Neuropathy Patient-Specific hiPSC-Derived Retinal Ganglion Cells

Glutamate Stimulation Dysregulates AMPA Receptors-Induced Signal Transduction Pathway in Leber’s Inherited Optic Neuropathy Patient-Specific hiPSC-Derived Retinal Ganglion Cells

Hereditary Optic Neuropathies: Induced Pluripotent Stem Cell-Based 2D/3D Approaches

Leber Hereditary Optic Neuropathy: Review of Treatment and Management

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