Abstract
BackgroundRetina diseases may lead to blindness as they often afflict both eyes. Stem cell transplantation into the affected eye(s) is a promising therapeutic strategy for certain retinal diseases. Human peripheral blood mononuclear cells (hPBMCs) are a good source of stem cells, but it is unclear whether pre-induced hPBMCs can migrate from the injected eye to the contralateral eye for bilateral treatment. We examine the possibility of bilateral cell transplantation from unilateral cell injection.MethodsOne hundred and sixty-one 3-month-old retinal degeneration 1 (rd1) mice were divided randomly into 3 groups: an untreated group (n = 45), a control group receiving serum-free Dulbecco’s modified Eagle’s medium (DMEM) injection into the right subretina (n = 45), and a treatment group receiving injection of pre-induced hPBMCs into the right subretina (n = 71). Both eyes were examined by full-field electroretinogram (ERG), immunofluorescence, flow cytometry, and quantitative real-time polymerase chain reaction (qRT-PCR) at 1 and 3 months post-injection.ResultsAt both 1 and 3 months post-injection, labeled pre-induced hPBMCs were observed in the retinal inner nuclear layer of the contralateral (left untreated) eye as well as the treated eye as evidenced by immunofluorescence staining for a human antigen. Flow cytometry of fluorescently label cells and qRT-PCR of hPBMCs genes confirmed that transplanted hPBMCs migrated from the treated to the contralateral untreated eye and remained viable for up to 3 months. Further, full-field ERG showed clear light-evoked a and b waves in both treated and untreated eyes at 3 months post-transplantation. Labeled pre-induced hPBMCs were also observed in the contralateral optic nerve but not in the blood circulation, suggesting migration via the optic chiasm.ConclusionIt may be possible to treat binocular eye diseases by unilateral stem cell injection.Graphical abstract
Highlights
Retina diseases may lead to blindness as they often afflict both eyes
It is reported that stem cells isolated from the adult mouse ciliary marginal zone can differentiate into specific retinal cells under appropriate culture conditions [11,12,13], while human and murine embryonic stem cells have been shown to differentiate into retinal pigment epithelial (RPE) cells as well as rhodopsinexpressing photoreceptor cells [14,15,16]
After 4 days, Human peripheral blood mononuclear cells (hPBMCs) were roughly classified into four categories: round cells, cells with one to three processes, cells aggregated in clusters, and large yellow cells (Supplemental Figure 1D-G)
Summary
Retina diseases may lead to blindness as they often afflict both eyes. Stem cell transplantation into the affected eye(s) is a promising therapeutic strategy for certain retinal diseases. Peripheral blood mononuclear cells (PBMCs) include a subpopulation of stem cells [20] showing multilineage differentiation potential under various induction conditions [21,22,23,24,25]. These cells can be isolated relatively and in large quantities, making them a promising potential source for cellbased therapy research and clinical application [26,27,28,29,30]. Human PBMCs co-cultured in vitro with neonatal rat retinas and transplanted into the subretinal space of RP model mice (rd mice) can survive for at least 3 months, distribute to all retinal layers, and partially restore lightevoked electrophysiological responses [31,32,33,34], demonstrating potential utility for RP treatment
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