Neuroprotective Effects of Human Mesenchymal Stem Cells and Platelet-Derived Growth Factor on Human Retinal Ganglion Cells

Abstract

Optic neuropathies such as glaucoma occur when retinal ganglion cells (RGCs) in the eye are injured. Strong evidence suggests mesenchymal stem cells (MSCs) could be a potential therapy to protect RGCs; however, little is known regarding their effect on the human retina. We, therefore, investigated if human MSCs (hMSCs), or platelet‐derived growth factor (PDGF) as produced by hMSC, could delay RGC death in a human retinal explant model of optic nerve injury. Our results showed hMSCs and the secreted growth factor PDGF‐AB could substantially reduce human RGC loss and apoptosis following axotomy. The neuroprotective pathways AKT, ERK, and STAT3 were activated in the retina shortly after treatments with labeling seen in the RGC layer. A dose dependent protective effect of PDGF‐AB was observed in human retinal explants but protection was not as substantial as that achieved by culturing hMSCs on the retina surface which resulted in RGC cell counts similar to those immediately post dissection. These results demonstrate that hMSCs and PDGF have strong neuroprotective action on human RGCs and may offer a translatable, therapeutic strategy to reduce degenerative visual loss. Stem Cells 2018;36:65–78

Mesenchymal stem cells: Cell therapy and regeneration potential

“…MSCs have shown promising outcomes in preclinical and clinical studies for treating pain and degenerative diseases such as AD, DDD, MS, PD, and RDD and providing immunomodulatory, neuroprotective, and anti‐inflammatory responses in vivo (Beeravolu et al, ; Ding, Kumar, & Mok, ; Gugliandolo, Bramanti, & Mazzon, ; Nasri et al, ; Osborne, Sanderson, & Martin, ; Perez‐Cruet et al, ; Turgeman, ; van Buul et al, ; R. Zhang, Liu, et al, ). Studies have shown that MSCs can be differentiated to NPCs to regenerate the NP in the IVD and to retinal progenitor cells to regenerate the retina within the eye (Beeravolu et al, ; Ding et al, ; Perez‐Cruet et al, ).…”

Retinal explant culture: A platform to investigate human neuro‐retina

“…The neuroprotective effective of different isoforms of PDGF (platelet‐derived growth factor) and hMSCs (human mesenchymal stem cells) were also successfully tested on human retinal explants following positive outcomes in animal models. The results indicated that both stimulate neuroprotective signalling pathways however, hMSCs are more suitable for neuroprotective therapies due to increased RGC survival induced by numerous neurotropic factors secreted by MSCs …”

“…A recent report indicates that photoreceptor precursor cells (PPCs) maturation is accelerated when co‐cultured in the presence of human retinal explants and hESC (human embryonic stem cell)‐derived pigmented epithelium . The hMSCs secrete neurotrophic factors which were shown to have neuroprotective effects on human retinal explants in culture …”

“…Explants obtained from every part of the retina have been successfully maintained in culture for an extended period. However, for experimental purposes, most studies have chosen para macular regions equidistant from the fovea so that each explant has a relatively uniform distribution of retinal cell types . This is the most suitable choice retinal experimentation as they produce reproducible retinal fragments.…”

A Preview of Selected Articles

“…While animal models of glaucoma and optic nerve injury indicate that retinal injections of platelet‐derived growth factor‐secreting human mesenchymal stem cells (hMSCs) support RGC survival and protect against vision loss, we understand little about the consequences of hMSC‐therapy in the human retina. A new S tem C ells study from Keith R. Martin (University of Cambridge, United Kingdom) sought to explore this therapeutic option via a novel approach whose findings correlates with the outcomes of in vivo therapies: a human retinal explant model of optic nerve injury . Following the severing of an RGC axon, Osborne et al established that hMSC therapy reduced RGC loss and promoted survival partly via the activation of neuroprotective AKT, ERK, and STAT3 signaling pathways.…”