Mitochondrial replacement in an iPSC model of Leber’s hereditary optic neuropathy

Wong, Raymond Ching-Bong; Lim, Shiang Y.; Hung, Stevephen; Jackson, Stacey; Khan, Shahnaz; Bergen, Nicole J Van; Smit, Elisabeth De; Liang, Helena; Kearns, Lisa S.; Clarke, Linda; Mackey, David A.; Hewitt, Alex W.; Trounce, Ian A.; Pébay, Alice

doi:10.18632/aging.101231

Cited by 43 publications

(28 citation statements)

References 26 publications

(32 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This study demonstrated that iPSCs can be obtained from LHON- fibroblasts with normal efficiency, thus suggesting that iPSC reprogramming can tolerate a certain degree of OXPHOS defects. A successful iPSC model for translational medicine was obtained by Wong et al [ 31 ], who used cybrid technology to replace mutated mitochondrial DNA (mtDNA) from LHON-specific fibroblasts with wildtype mtDNA. The authors obtained mutation-free iPSCs and in these cybrid corrected iPSC-derived retinal ganglion cell, the cell death phenotype was res cued.…”

Section: Discussionmentioning

confidence: 99%

Senescence-associated ultrastructural features of long-term cultures of induced pluripotent stem cells (iPSCs)

Colasuonno

Borghi

Niceforo

et al. 2017

Aging

View full text Add to dashboard Cite

Induced pluripotent stem cells (iPSCs) hold great promise for developing personalized regenerative medicine, however characterization of their biological features is still incomplete. Moreover, changes occurring in long-term cultured iPSCs have been reported, suggesting these as a model of cellular aging. For this reason, we addressed the ultrastructural characterization of iPSCs, with a focus on possible time-dependent changes, involving specific cell compartments. To this aim, we comparatively analysed cultures at different timepoints, by an innovative electron microscopic technology (FIB/SEM). We observed progressive loss of cell-to-cell contacts, associated with increased occurrence of exosomes. Mitochondria gradually increased, while acquiring an elongated shape, with well-developed cristae. Such mitochondrial maturation was accompanied by their turnover, as assessed by the presence of autophagomes (undetectable in young iPSCs), some containing recognizable mitochondria. This finding was especially frequent in middle-aged iPSCs, while being occasional in aged cells, suggesting early autophagic activation followed by a decreased efficiency of the process with culturing time. Accordingly, confocal microscopy showed age-dependent alterations to the expression and distribution of autophagic markers. Interestingly, responsivity to rapamycin, highest in young iPSCs, was almost lost in aged cells. Overall, our results strongly support long-term cultured iPSCs as a model for studying relevant aspects of cellular senescence, involving intercellular communication, energy metabolism, and autophagy.

show abstract

Section: Discussionmentioning

confidence: 99%

Senescence-associated ultrastructural features of long-term cultures of induced pluripotent stem cells (iPSCs)

Colasuonno

Borghi

Niceforo

et al. 2017

Aging

View full text Add to dashboard Cite

show abstract

“…All these data reporting, selection, maturation and/or functional assessment of human PSC-derived RGCs should allow to study patient-derived iPSC lines, for a better understanding of ocular disease related to RGC impairment. In this context, different groups have already derived iPSCs from somatic cells of patients diagnosed for different optic neuropathies ( Chen et al, 2016 ; Ohlemacher et al, 2016 ; Teotia et al, 2017 ; Wong et al, 2017 ) ( Table 3 ). For example, the generation of LHON-patient iPSC allowed the exploration of oxidative phosphorylation defect ( Hung et al, 2016 ).…”

Section: Pluripotent-stem Cells-derived Rgcsmentioning

confidence: 99%

“…For example, the generation of LHON-patient iPSC allowed the exploration of oxidative phosphorylation defect ( Hung et al, 2016 ). In a more recent study, the same group demonstrated that replacing LHON mitochondrial DNA using cybrid technology in patient iPSCs can prevented the death of iPSC-derived RGCs ( Wong et al, 2017 ). Another iPSC line carrying mutation in the Optineurin ( OPTN ) gene has been recently derived ( Ohlemacher et al, 2016 ) and higher cell death of iPSC-derived RGCs carrying the mutation has been observed.…”

Section: Pluripotent-stem Cells-derived Rgcsmentioning

confidence: 99%

Pluripotent Stem Cell-Based Approaches to Explore and Treat Optic Neuropathies

2018

View full text Add to dashboard Cite

Sight is a major sense for human and visual impairment profoundly affects quality of life, especially retinal degenerative diseases which are the leading cause of irreversible blindness worldwide. As for other neurodegenerative disorders, almost all retinal dystrophies are characterized by the specific loss of one or two cell types, such as retinal ganglion cells, photoreceptor cells, or retinal pigmented epithelial cells. This feature is a critical point when dealing with cell replacement strategies considering that the preservation of other cell types and retinal circuitry is a prerequisite. Retinal ganglion cells are particularly vulnerable to degenerative process and glaucoma, the most common optic neuropathy, is a frequent retinal dystrophy. Cell replacement has been proposed as a potential approach to take on the challenge of visual restoration, but its application to optic neuropathies is particularly challenging. Many obstacles need to be overcome before any clinical application. Beyond their survival and differentiation, engrafted cells have to reconnect with both upstream synaptic retinal cell partners and specific targets in the brain. To date, reconnection of retinal ganglion cells with distal central targets appears unrealistic since central nervous system is refractory to regenerative processes. Significant progress on the understanding of molecular mechanisms that prevent central nervous system regeneration offer hope to overcome this obstacle in the future. At the same time, emergence of reprogramming of human somatic cells into pluripotent stem cells has facilitated both the generation of new source of cells with therapeutic potential and the development of innovative methods for the generation of transplantable cells. In this review, we discuss the feasibility of stem cell-based strategies applied to retinal ganglion cells and optic nerve impairment. We present the different strategies for the generation, characterization and the delivery of transplantable retinal ganglion cells derived from pluripotent stem cells. The relevance of pluripotent stem cell-derived retinal organoid and retinal ganglion cells for disease modeling or drug screening will be also introduced in the context of optic neuropathies.

show abstract

“…Induced pluripotent stem cells can now be routinely produced by reprogramming peripheral blood cells or fibroblasts obtained from a punch skin biopsy [ 43 ]. In parallel, differentiation protocols are being refined by a number of research groups worldwide to allow the efficient generation of various retinal cells, including RGCs, providing an ideal ‘disease in a dish’ model for testing promising drug molecules in a more physiological setting [ 44 – 46 ].…”

Section: Therapeutic Drug Screeningmentioning

confidence: 99%

Leber hereditary optic neuropathy

Jurkutė¹,

Yu‐Wai‐Man²

2017

Current Opinion in Ophthalmology

View full text Add to dashboard Cite

Purpose of reviewLeber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) genetic disorder in the population. We address the clinical evolution of the disease, the secondary etiological factors that could contribute to visual loss, and the challenging task of developing effective treatments.Recent findingsLHON is characterized by a preclinical phase that reflects retinal ganglion cell (RGC) dysfunction before rapid visual deterioration ensues. Children can present atypically with slowly progressive visual loss or an insidious/subclinical onset that frequently results in considerable diagnostic delays. The LHON mtDNA mutation is not sufficient on its own to precipitate RGC loss and the current body of evidence supports a role for smoking and estrogen levels influencing disease conversion. Clinical trials are currently investigating the efficacy of adeno-associated viral vectors-based gene therapy approaches for patients carrying the m.11778G>A mutation. Mitochondrial replacement therapy is being developed as a reproductive option to prevent the maternal transmission of pathogenic mtDNA mutations.SummaryLHON is phenotypically more heterogeneous than previously considered and a complex interplay of genetic, environmental and hormonal factors modulates the risk of a LHON carrier losing vision. Advances in disease modelling, drug screening and genetic engineering offer promising avenues for therapeutic breakthroughs in LHON.

show abstract

Mitochondrial replacement in an iPSC model of Leber’s hereditary optic neuropathy

Cited by 43 publications

References 26 publications

Senescence-associated ultrastructural features of long-term cultures of induced pluripotent stem cells (iPSCs)

Senescence-associated ultrastructural features of long-term cultures of induced pluripotent stem cells (iPSCs)

Pluripotent Stem Cell-Based Approaches to Explore and Treat Optic Neuropathies

Leber hereditary optic neuropathy

Contact Info

Product

Resources

About