Abstract
Adipose-derived stem cells (ASCs) have shown a strong protective effect on retinal degenerative diseases (RDD) after being transplanted into the subretinal space in an animal model. Recently, several clinical trials have been conducted to treat RDD with intravitreal transplantation of stem cells, including ASCs. However, the outcomes of the clinical trials were not satisfactory. To investigate if the transplantation site alters the outcome of stem cell-based therapy for RDD, we isolated rat ASCs (rASCs) and labeled them with green fluorescent protein. Autologous rASCs were grafted into the vitreous chamber or subretinal space in a rat RDD model induced by sodium iodate (SI). The electric response was recorded by ERG. The anatomic structure of the retina was observed in cryosections of rat eyes at posttransplantation weeks 1, 2, and 4. Neural retina apoptosis and epiretinal membrane- (ERM-) like structure formation were investigated by immunostaining. The intravitreal transplantation of rASCs resulted in an extinguished electric response, although the rosette formation and apoptosis of neural retina were reduced. However, the rASCs that grafted in the subretinal space protected the retina from the damage caused by SI, including a partial recovering of the electric response and a reduction in rosette formation. Intravitreally grafted rASCs formed a membrane, resulting in retina folding at the injection site. Müller cells, retinal pigment epithelial cells, and microglial cells migrated from the retina to the rASC-formed membrane and subsequently formed an ERM-like structure. Furthermore, vitreous fluid promoted rASC migration, and rASC-conditioned medium enhanced Müller cell migration as indicated by in vitro studies. These data suggested that the vitreous chamber is not a good transplantation site for ASC-based therapy for RDD and that a deliberate decision should be made before transplantation of stem cells into the vitreous chamber to treat RDD in clinical trials.
Highlights
Retinal degenerative diseases (RDD), including age-related macular degeneration (AMD) and retinitis pigmentosa (RP), are one of the leading causes of blindness worldwide [1, 2]
To evaluate the effect of rat ASCs (rASCs) grafted into the vitreous chamber on SIinduced damage to the retina, we established a rat RDD model by intravenous infusion of sodium iodate (SI), and rASCs were autografted into the vitreous chamber
We investigated if the subretinal space is the proper transplantation site for stem cell-based therapy for RDD. rASCs were autografted into the subretinal space in SIinduced RDD rats. b-wave amplitudes were markedly increased in the rASC treatment group compared with the phosphate-buffered saline (PBS) group (Figures 3(a) and 3(b)), and retinas with transplanted rASCs maintained better anatomic structures compared with the PBS group (Figure 3(c))
Summary
Retinal degenerative diseases (RDD), including age-related macular degeneration (AMD) and retinitis pigmentosa (RP), are one of the leading causes of blindness worldwide [1, 2]. The outcomes of several clinical trials have shown that some patients who received intravitreal transplantation of human ASCs have dense vitreous hemorrhage in the eyes, retinal detachment with severe proliferative vitreoretinopathy (PVR), and secondary epiretinal membrane (ERM) formation [16, 17]. These complications are sometimes associated with the surgery. More studies showed that intravitreal transplantation of other kinds of stem cells resulted in ERM formation [18,19,20], which suggest that surgery process and transplantation sites may affect therapeutic outcomes. Epiretinal membrane formation was investigated to demonstrate a potential secondary complication of ASC treatment of RDD, providing critical information for future clinical trials
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