Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin

Abstract

With recent progress in neuroscience and stem-cell research, neural transplantation has emerged as a promising therapy for treating CNS diseases. The success of transplantation has been limited, however, by the restricted ability of neural implants to survive and establish neuronal connections with the host. Little is known about the mechanisms responsible for this failure. Neural implantation triggers reactive gliosis, a process accompanied by upregulation of intermediate filaments in astrocytes and formation of astroglial scar tissue. Here we show that the retinas of adult mice deficient in glial fibrillary acidic protein and vimentin, and consequently lacking intermediate filaments in reactive astrocytes and Müller cells, provide a permissive environment for grafted neurons to migrate and extend neurites. The transplanted cells integrated robustly into the host retina with distinct neuronal identity and appropriate neuronal projections. Our results indicate an essential role for reactive astroglial cells in preventing neural graft integration after transplantation.

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

“…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.…”

“…However, one of the unaddressed obstacles is the gliotic response that astrocytes and Muller glia (non‐neuronal support cells within the retina) exhibit in response to grafted cells 4, 5, 6. In retinal cell neuroprotection and replacement therapy, the glial response to the donor cell graft is an important barrier to overcome in order to enhance synaptic plasticity and axonal remodeling of surviving neurons as well as integration of a variety of donor cell types into the host retinal circuitry 4, 5, 7, as shown in the outer 5 and inner retina 4, 8, 9.…”

“…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.…”

BDNF-treated retinal progenitor sheets transplanted to degenerate rats: Improved restoration of visual function

“…Although various techniques have been performed to promote the neuronal integration between the transplant and the host retina (Kinouchi et al, 2003;Lavik et al, 2005), no clear evidence of functional synaptic connectivity has yet been published. However, preliminary data from our group have shown that neurons in the transplant can be trans-synaptically labeled from the visually responsive site in the SC (Seiler et al, 2005b; manuscript submitted).…”

Prefractionation of Cerebrospinal Fluid to Enhance Glycoprotein Concentration Prior to Structural Determination with FT−ICR Mass Spectrometry

“…GFAP -/-Vim -/-mice show slower wound healing and reduced glial scaring after brain or spinal cord trauma (105). The Pekny group and others have previously reported improved regeneration in GFAP -/-Vim -/-mice, specifically axonal regeneration (106), (107), survival and integration of neuronal grafts in the retina (108) or improved synaptic regeneration in the denervated dentate gyrus of the hippocampus (109), for a review see (102).…”