Rebuilding the Retina: Prospects for Müller Glial-mediated Self-repair

Abstract

Retinal degeneration is a leading cause of untreatable blindness in the industrialised world. It is typically irreversible and there are few curative treatments available. The use of stem cells to generate new retinal neurons for transplantation purposes has received significant interest in recent years and is beginning to move towards clinical trials. However, such approaches are likely to be most effective for relatively focal areas of repair. An intriguing complementary approach is endogenous self-repair. Retinal cells from the ciliary marginal zone (CMZ), retinal pigment epithelium (RPE) and Müller glial cells (MG) have all been shown to play a role in retinal repair, typically in lower vertebrates. Among them, MG have received renewed interest, due to their distribution throughout (centre to periphery) the neural retina and their potential to re-acquire a progenitor-like state following retinal injury with the ability to proliferate and generate new neurons. Triggering these innate self-repair mechanisms represents an exciting therapeutic option in treating retinal degeneration. However, these cells behave differently in mammalian and non-mammalian species, with a considerably restricted potential in mammals. In this short review, we look at some of the recent progress made in our understanding of the signalling pathways that underlie MG-mediated regeneration in lower vertebrates, and some of the challenges that have been revealed in our attempts to reactivate this process in the mammalian retina. ARTICLE HISTORY Endogenous repair mechanisms CMZ-mediated repairThe CMZ in zebrafish and frogs is well defined and comprised of the ciliary body and the ciliary zone. The ciliary zone consists of

Management of retinitis pigmentosa by Wharton’s jelly derived mesenchymal stem cells: preliminary clinical results

“…Molecules greater than 75 kDa can be dispersed through the sclera by changing the electrical charges using electrical/electromagnetic iontophoresis such as Magnovision™ [59][60][61][62][63][64]. Growth factors secreted by MSCs in the subretinal space activate the cells in the dormant phase and stimulate the progenitor cells (embriyonic remnants) in the retina [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]29]. We preferred to use the deep sub-tenon space as a microenvironment in order to prevent the devastating adverse effects of intravitreal/subretinal injection.…”

“…WJ-MSCs have been shown to suppress chronic inflammation and prevent apoptosis in animal models of neurodegenerative and ischemic retinal disorders [27,28]. WJ-MSCs also stimulate progenitor cells in the retina and elicit selfrepair mechanisms [29,30].…”

Management of retinitis pigmentosa by Wharton’s jelly-derived mesenchymal stem cells: prospective analysis of 1-year results

“…These secreted exosomes include growth factors, cytokines, mRNA sequences, microRNA, and mitochondrial components [53][54][55][56][57][58][59][60][61]. The growth factors and mitochondrial content of exosomes stimulate cellular oxidative phosphorylation and the cellular energy cycle, thus, providing regenerative and restorative effects for the microenvironment [62,63]. Neural growth factor (NGF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) are the main exosome contents that affect the outer retinal layers.…”

Regeneration of Functional Retinal Ganglion Cells by Neuronal Identity Reprogramming

“…By contrast, Müller glia in mammals do not have this capacity and mammals, including humans, also do not have other reservoirs of retinal stem/progenitor cells poised to regenerate retinal neurons in the adult stage (Cicero et al, 2009;Langhe and Pearson, 2019). The current consensus is that there is normally little to no ongoing addition of neurons in the mature mammalian retina.…”