Chondroitin Sulfate Proteoglycans and Microglia Prevent Migration and Integration of Grafted Müller Stem Cells into Degenerating Retina

Abstract

ABSTRACT

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. 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.…”

Stem Cell Based Therapies for Glaucoma

“…Engrafted cells were shown to express the photoreceptor markers recoverin and rhodopsin, the RGC marker HuD as well as calretinin, which identifies RGCs and amacrine cells (Lawrence et al, 2007). Although integration of undifferentiated Müller stem cells has been observed after subretinal transplantation into adult dystrophic RCS rats, these cells were located in all retinal layers and did not selectively locate to the ganglion cell layer or adopt RGC-like morphology (Singhal et al, 2008).…”

Transplantation prospects for the inner retina

“…Treatment with chondroitinase ABC, for instance, digests chondroitin sulphate proteoglycans and enhances neurite outgrowth in the spinal cord 36 and in the retina. 17,37 Combination treatments that promote migration, neurite growth, and synaptogenesis may be required for the full integration of transplanted cells. Thus, although formidable obstacles remain before cell transplantation will be used clinically to treat inner retinal disease, stepwise progress is leading us closer to protocols that may eventually demonstrate efficacy.…”