Grafted c-kit+/SSEA1− eye-wall progenitor cells delay retinal degeneration in mice by regulating neural plasticity and forming new graft-to-host synapses

Abstract

BackgroundDespite diverse pathogenesis, the common pathological change observed in age-related macular degeneration and in most hereditary retinal degeneration (RD) diseases is photoreceptor loss. Photoreceptor replacement by cell transplantation may be a feasible treatment for RD. The major obstacles to clinical translation of stem cell-based cell therapy in RD remain the difficulty of obtaining sufficient quantities of appropriate and safe donor cells and the poor integration of grafted stem cell-derived photoreceptors into the remaining retinal circuitry.MethodsEye-wall c-kit+/stage-specific embryonic antigen 1 (SSEA1)− cells were isolated via fluorescence-activated cell sorting, and their self-renewal and differentiation potential were detected by immunochemistry and flow cytometry in vitro. After labeling with quantum nanocrystal dots and transplantation into the subretinal space of rd1 RD mice, differentiation and synapse formation by daughter cells of the eye-wall c-kit+/SSEA1− cells were evaluated by immunochemistry and western blotting. Morphological changes of the inner retina of rd1 mice after cell transplantation were demonstrated by immunochemistry. Retinal function of rd1 mice that received cell grafts was tested via flash electroretinograms and the light/dark transition test.ResultsEye-wall c-kit+/SSEA1− cells were self-renewing and clonogenic, and they retained their proliferative potential through more than 20 passages. Additionally, eye-wall c-kit+/SSEA1− cells were capable of differentiating into multiple retinal cell types including photoreceptors, bipolar cells, horizontal cells, amacrine cells, Müller cells, and retinal pigment epithelium cells and of transdifferentiating into smooth muscle cells and endothelial cells in vitro. The levels of synaptophysin and postsynaptic density-95 in the retinas of eye-wall c-kit+/SSEA1− cell-transplanted rd1 mice were significantly increased at 4 weeks post transplantation. The c-kit+/SSEA1− cells were capable of differentiating into functional photoreceptors that formed new synaptic connections with recipient retinas in rd1 mice. Transplantation also partially corrected the abnormalities of inner retina of rd1 mice. At 4 and 8 weeks post transplantation, the rd1 mice that received c-kit+/SSEA1− cells showed significant increases in a-wave and b-wave amplitude and the percentage of time spent in the dark area.ConclusionsGrafted c-kit+/SSEA1− cells restored the retinal function of rd1 mice via regulating neural plasticity and forming new graft-to-host synapses.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0451-8) contains supplementary material, which is available to authorized users.

SCF/SCFR signaling plays an important role in the early morphogenesis and neurogenesis of human embryonic neural retina

“…The SCFR + donor cells survive up to 6 months in the subretinal space of host retina without generating teratoma. More importantly, in addition to robust material transfer and perfect cell replacement, these donor cells greatly inhibit the activation of microglia cells and improve the immune microenvironment of the RP disease (Chen et al, 2016;Zou et al, 2019). Our data well support the idea of SCFR + RPCs from a developmental view, and partially explain the advantages for transplantation, such as retinal multipotency, limited proliferation, strong survivability and proper migration.…”

KIT ligand produced by limbal niche cells under control of SOX10 maintains limbal epithelial stem cell survival by activating the KIT/AKT signalling pathway

“…55 Interestingly, KIT is not only expressed in LESCs but also in photoreceptors, lacrimal canaliculus epithelial stem cells and eye wall cells. [56][57][58] These cells are all essential for sustaining the physiological functions of the eye and are located in close proximity to SOX10-positive NCCs or their derivatives. 24 Hence, the SOX10-KIT-AKT axis may have a role in eye development and function beyond its role in maintaining LESCs that we demonstrated here.…”

Otx2 enhances transdifferentiation of Müller cells‐derived retinal stem cells into photoreceptor‐like cells

“…To characterize cell communication and gap junctions of photoreceptor‐like cells, we selected specific synaptic vesicle protein Synaptophysin to label the synaptic connections between regenerated photoreceptor‐like cells and adjacent neurons . Immunofluorescence assay showed that synaptophysin presented a multi‐layer distribution in the outer plexiform photoreceptor cells at the end and within the plexiform layer.…”