Abstract
Retinal degenerative diseases (RDDs) are the leading causes of blindness and currently lack effective treatment. Cytotherapy has become a promising strategy for RDDs. The transplantation of olfactory ensheathing cells (OECs) or neural stem cells (NSCs) has recently been applied for the experimental treatment of RDDs. However, the long-term outcomes of single-cell transplantation are poor. The combined transplantation of multiple types of cells might achieve better effects. In the present study, OECs [containing olfactory nerve fibroblasts (ONFs)] and NSCs were cotransplanted into the subretinal space of Royal College of Surgeons (RCS) rats. Using electroretinogram (ERG), immunofluorescence, Western blot, and in vitro Transwell system, the differences in the electrophysiological and morphological changes of single and combined transplantation as well as the underlying mechanisms were explored at 4, 8, and 12 weeks postoperation. In addition, using the Transwell system, the influence of OECs on the stemness of NSCs was discovered. Results showed that, compared to the single transplantation of OECs or NSCs, the combined transplantation of OECs and NSCs produced greater improvements in b-wave amplitudes in ERGs and the thickness of the outer nuclear layer at all three time points. More endogenous stem cells were found within the retina after combined transplantation. Glial fibrillary acidic protein (GFAP) expression decreased significantly when NSCs were cotransplanted with OECs. Both the vertical and horizontal migration of grafted cells were enhanced in the combined transplantation group. Meanwhile, the stemness of NSCs was also better maintained after coculture with OECs. Taken together, the results suggested that the combined transplantation of NSCs and OECs enhanced the improvement in retinal protection in RCS rats, providing a new strategy to treat RDDs in the future.
Highlights
Characterized by the progressive loss or malfunction of retinal cells, retinal degenerative diseases (RDDs) are the leading causes of blindness
We found that nearly half of the olfactory ensheathing cells (OECs)/olfactory nerve fibroblasts (ONFs) mixture expressed P75, and the other half expressed FN (Supplementary Figures 3C–E)
Flow cytometry showed that a high percentage of neural stem cells (NSCs) expressed Sox2 (98.86%), Pax6 (98.94%), and Nestin (98.38%) (Supplementary Figure 4E)
Summary
Characterized by the progressive loss or malfunction of retinal cells, retinal degenerative diseases (RDDs) are the leading causes of blindness. Characterized by the inability of RPE to phagocytose photoreceptor outer segments, RCS rat is the first known animal with inherited retinal degeneration (Strauss et al, 1998). The mutation in this model is found to be the deletion in the receptor tyrosine kinase gene Mertk, which links to the phagocytosing function of RPE (D’Cruz et al, 2000). Since its pathology is similar to RDDs, RCS rat is widely used as an animal model to mimic AMD and retinitis pigmentosa (LaVail, 2001). The response of electroretinograms (ERGs) in RCS rat begin to decrease at postnatal 21 days, reduce by half at postnatal 50 days, and nearly disappear at postnatal 100 days (Pinilla et al, 2005)
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