Repair of the degenerate retina by photoreceptor transplantation

Abstract

Despite different aetiologies, age-related macular degeneration and most inherited retinal disorders culminate in the same final common pathway, the loss of photoreceptors. There are few treatments and none reverse the loss of vision. Photoreceptor replacement by transplantation is proposed as a broad treatment strategy applicable to all degenerations. Recently, we demonstrated restoration of vision following rod-photoreceptor transplantation into a mouse model of stationary night-blindness, raising the critical question of whether photoreceptor replacement is equally effective in different types and stages of degeneration. We present a comprehensive assessment of rod-photoreceptor transplantation across six murine models of inherited photoreceptor degeneration. Transplantation is feasible in all models examined but disease type has a major impact on outcome, as assessed both by the morphology and number of integrated rod-photoreceptors. Integration can increase (Prph2

Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation

“…Reactive gliosis represents a barrier to successful stem cell‐based strategies in several neuropathological conditions 4, 5, 13, 37, 38. In an animal model of retinal degeneration both subretinal and intravitreal stem cell transplantation resulted in strong reactive gliosis and chondroitin sulfate proteoglycan deposition limiting stem cell migration into the host tissue 4, 5, 8, 12.…”

“…Reactive gliosis represents a barrier to successful stem cell‐based strategies in several neuropathological conditions 4, 5, 13, 37, 38. In an animal model of retinal degeneration both subretinal and intravitreal stem cell transplantation resulted in strong reactive gliosis and chondroitin sulfate proteoglycan deposition limiting stem cell migration into the host tissue 4, 5, 8, 12. This effect appeared to be independent of the type and origin of stem cells transplanted and, consistent with our study, was observed with both heterologous and autologous stem cell sources including Muller stem cells 12, photoreceptor precursors 5, neuronal progenitors 9, induced pluripotent stem cells 10, 11, and MSCs 4, 39.…”

“…In an animal model of retinal degeneration both subretinal and intravitreal stem cell transplantation resulted in strong reactive gliosis and chondroitin sulfate proteoglycan deposition limiting stem cell migration into the host tissue 4, 5, 8, 12. This effect appeared to be independent of the type and origin of stem cells transplanted and, consistent with our study, was observed with both heterologous and autologous stem cell sources including Muller stem cells 12, photoreceptor precursors 5, neuronal progenitors 9, induced pluripotent stem cells 10, 11, and MSCs 4, 39. Here, we offer a detailed investigation of retina glial responses to intravitreal BM‐MSC transplantation in order to identify molecular mechanisms behind graft‐induced reactive gliosis in the retina.…”

“…Furthermore, understanding of the host glial response following donor cell transplantation into the eye could be more broadly informative within the field of stem cell regenerative research for the development of more efficient and successful therapies. Indeed, reactive gliosis following transplantation is not limited to MSCs, but it occurs in response to many other donor cell types, including neuronal cells 9 induced pluripotent cells 10, 11, Muller stem cells 12, and photoreceptor precursors 5, transplanted either into the vitreous or in the subretinal space for regenerative and protective purposes. Moreover, similar hostile glial responses are not confined to the retina and the optic nerve but have also been observed in other part of the CNS, such as in the spinal cord following Schwann cell transplantation at the site of injury 13.…”

Bimodal in vivo imaging provides early assessment of stem-cell-based photoreceptor engraftment

“…Remarkably, a handful of studies have shown some restoration of vision in photoreceptor precursor cell (PPC) recipients, [6][7][8][9] though graft integration and survival remains too low to be clinically relevant. Short-term assessment in serial studies aimed at addressing these barriers currently relies on imaging, such as ophthalmoscopy and end point histology.…”