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

Abstract

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.

Hereditary Optic Neuropathies: A Systematic Review on the Interplay between Biomaterials and Induced Pluripotent Stem Cells

“…Many studies have focused on the exploration of technology for the induced differentiation of iPSCs into RGCs, and a series of breakthroughs have been made in the past decade [80]. In fact, several differentiation protocols with diverse strategies have already been developed to generate RGCs from iPSCs in 2D systems [81]. Human RGCs can also be created in human stem cell-derived retinal organoids; however, during long-term organoid culture, RGCs are predominantly lost, limiting studies of RGC maturation and functionality in vitro [82].…”

“…According to recent studies, supporting materials and carriers would help in the procurement, transplantation, and adaptation of differentiated cells created from iPSCs and other stem cells by providing physical and chemical cues that guide the differentiation of these and other stem cells and stabilize the target cell types, for example, against oxidations due to reactive oxygen species (ROS), which result in apoptosis in most cases [81]. In the last few years, there has been increasing evidence reported on the importance of decellularized extracellular matrix (dEMC) biomaterials, synthetic polymers, and natural hydrogels based on polysaccharides and/or proteins, either alone or in combination with very active small molecules.…”

Appropriate patient population for future visual system axon regeneration therapies

“…Peripheral nerve regeneration studies suggest some molecules capable of reducing negative environmental effects (Delibas et al, 2021) that may be potentially repurposed for the ON after various injuries. Stem cell therapies are also emerging, including neural, mesenchymal, and induced pluripotent stem cells (Garcia‐Lopez et al, 2021; Limoli et al, 2021; Zhang et al, 2016). Despite promising results in preclinical studies, further research is needed to fully understand the potential benefits and risks of such therapies for axon regeneration in the human optic nerve.…”

Retinal Ganglion Cell Transplantation: Approaches for Overcoming Challenges to Functional Integration

“…Acquired toxic or nutritional optic neuropathies, for instance, might be amenable to removal of the inciting agent and are therefore associated with a more receptive microenvironment. Hereditary conditions, such as Leber optic neuropathy or autosomal dominant optic atrophy, are candidates for gene therapy correction of the donor RGCs [134] if autologous cells are transplanted. To the extent that RGC death itself creates secondary neurotoxic effects, however, any therapeutic RGC transplant may face environmental challenges.…”