Abstract
Retinal degeneration is characterized by the progressive loss of photoreceptors, and stem cell therapy has become a promising strategy. Many studies have reported that mesenchymal stem cell transplantation can sustain retinal structure and prolong retinal functions based on two mechanisms. One is cell replacement, and the other is the paracrine action of stem cells. Cells from human exfoliated deciduous teeth (SHEDs) show characteristics typical of mesenchymal stem cells. They are derived from the neural crest and are a potential cellular source for neural regeneration in stem cell therapy. In this study, we explored the potential of SHEDs to be induced towards the retinal photoreceptor phenotype and to be sustainable in an animal model of retinal degeneration. A factor-cocktail protocol was used to induce SHEDs towards retinal photoreceptors for 24 days, and the characteristics of the induced cells were identified in terms of morphological changes, biomarker expression and subcellular distribution, and calcium influx. SHEDs were labeled with firefly luciferase for in vivo tracking by bioluminescent imaging and then transplanted into the subretinal space of mice. Our results showed that SHEDs successfully transdifferentiated into photoreceptor-like cells, which displayed neuron-like morphology, and expressed specific genes and proteins associated with retinal precursors, photoreceptor precursors, and mature photoreceptors. In addition, calcium influx was significantly greater in the retinal-induced than in noninduced SHEDs. In vivo tracking confirmed at least 2 weeks of good survival by bioluminescent imaging and 3 months of sustainability of SHEDs by histological analysis. We conclude that SHEDs have the potential to transdifferentiate into retinal photoreceptor-like cells in vitro and maintain good viability in vivo after transplantation into mice with a normal immune system. This demonstrates preliminary success in generating photoreceptor-like cells from SHEDs and applying SHEDs in treating retinal degeneration.
Highlights
Retinal degeneration associated with photoreceptor loss causes visual impairment and even untreatable blindness, affecting millions of people
Stem cell therapy is a prospective strategy for treating retinal degeneration [1, 2], and finding an ideal source of stem cells for transplantation is a key issue for this field
Dickkopf-related protein 1 (DKK-1) antagonizes Wnt/β catenin signaling, and noggin inhibits BMP signaling; these two key factors are essential for inducing SHEDs toward retinal photosensory cells
Summary
Retinal degeneration associated with photoreceptor loss causes visual impairment and even untreatable blindness, affecting millions of people. Human retinal neurons have a limited ability to repair themselves or regenerate, especially the photoreceptors (rods and cones) which are terminal sensory neurons connected to the first cranial nerve (optic nerve). Stem cell therapy is a prospective strategy for treating retinal degeneration [1, 2], and finding an ideal source of stem cells for transplantation is a key issue for this field. Different approaches to retinal regeneration have been explored. One important strategy is to use cells or tissues derived in vitro to replace injured retinal cells by transplantation. Photoreceptors derived from human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPS cells) and engineered retinal tissues have shown great potential to repair the structure and function of damaged retinal tissues in animal models of retinal degeneration. Human adult stem cells without these concerns are emerging as a promising approach
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