Abstract

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.

Highlights

  • Sight is defined first as the faculty to detect light, enabling to form an image of the environment

  • Vision impairment is disabling, Human induced pluripotent stem cells (iPSCs)-Derived Retinal Ganglion Cells especially irreversible and untreatable blindness that is often due to degeneration of the retina, the light-sensitive tissue located at the back of the eye

  • Cockayne syndrome related to mutations in genes involved in DNA repair cannot be considered as an optic neuropathy disease, phenotypic analysis of several cases showed a loss of retinal ganglion cell (RGC) and degeneration of the optic nerve in some patients (Weidenheim et al, 2009)

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Summary

INTRODUCTION

Sight is defined first as the faculty to detect light (non-image forming visual functions), enabling to form an image of the environment (image forming visual function). Thomson obtained similar results with a slightly different combination of reprogramming factors comprising OCT4, SOX2, Nanog homeobox (NANOG) and Lin-28 homolog A (LIN28) (Yu et al, 2007) These cells, named induced pluripotent stem cells (iPSCs) display almost all the ESC features and represent an incredibly promising source of cells for transplantation approaches. In addition to BDNF, many other neurotrophic factors such as Nerve Growth Factor (NGF), Glial cell-Derived Neurotrophic Factor, Insulinlike Growth Factor-1 (IGF-1) or Leukemia Inhibitory Factor (Yan et al, 1999; Kermer et al, 2000; Mao et al, 2008; Leibinger et al, 2009; Kimura et al, 2016), have been reported to delay or prevent RGC death In this context, acute glial cell activation is involved in neuroprotection via the delivery of trophic support but depending on the kinetic of glial activation. Acute activation of glial cells is believe to mediate neuroprotection via the delivery of trophic support but chronic gliosis may be essentially neurotoxic via inflammatory mechanisms (Almasieh et al, 2012; Munemasa and Kitaoka, 2013; Vecino et al, 2016)

LHON and DOA
RETINAL DEVELOPMENT
Generation of RGC From Mouse PSCs
RGC identification
RGC isolation
Generation of RGCs From Human PSCs
RGC maturation conditions
RPE RGCs
Pluripotent Stem Cells
Endogenous Regeneration Capacity
PERSPECTIVES AND FUTURE DIRECTIONS
Findings
AUTHOR CONTRIBUTIONS
Full Text
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