Abstract
Retinal disease treatment by stem cell-based replacement relies on stem cell differentiation into retinal cells. We previously demonstrated that human periodontal ligament-derived stem cells can be directed into retinal lineage upon induction. Here, we report the transdifferentiation potential of human adipose-derived stem cells (ASCs) into retinal lineage and its enhancement by Notch signaling modulation. Human ASCs, isolated from abdominal fat, expressed mesenchymal but not hematopoietic stem cell markers, and they can differentiate into adipocytes, chondrocytes, and osteoblasts in vitro. Upon noggin/Dkk-1/IGF-1 induction, the treated ASCs showed elevated expression of retinal progenitor, retinal ganglion, and photoreceptor cell markers as well as the glutamate-evoked calcium response, which was not observed in the noninduced cells. Compared to the regular induction treatment, Notch signaling activation by JAG1 enhanced the expression of retinal progenitor and precursor markers without affecting the glutamate-evoked calcium response. In contrast, Notch signaling inhibition by DAPT showed more retinal ganglion cells, but delayed the response to glutamate stimulation. In summary, our results revealed that human ASCs possess a retinal transdifferentiation potential upon noggin/Dkk-1/IGF-1 induction, which can further be enhanced by Notch signaling activation.
Highlights
Retinal diseases, including age-related macular degeneration, glaucoma, diabetic retinopathy, and retinitis pigmentosa, are the leading causes of irreversible blindness and visual impairment, affecting more than 300 million people worldwide
Human adipose-derived stem cells (ASCs) were maintained in ADSC-BM medium (Lonza) supplemented with 10% fetal bovine serum (FBS; Gibco), 1% glutamine, and 0.1% antibiotics GA-1000
Human ASCs were first characterized by the expression of mesenchymal stem cell (MSC) (CD44, CD73, CD90, and CD105) and hematopoietic stem cell (HSC) (CD14, CD34, and CD45) markers
Summary
Retinal diseases, including age-related macular degeneration, glaucoma, diabetic retinopathy, and retinitis pigmentosa, are the leading causes of irreversible blindness and visual impairment, affecting more than 300 million people worldwide. The human retina has limited intrinsic regenerative capability, and current treatment regimens are not sufficient for functional repair of the diseased retinal cells. Stem cell-based replacement, which relies on the differentiation of stem cells into retinal cells, could be a potential strategy for retinal disease treatment [1, 2]. The studies on human adult stem cells, which can be conveniently obtained for autologous transplantation, for retinal differentiation are limited. We have established protocols to direct human periodontal ligament-derived stem cells (PDLSCs) into retinal lineage by inhibiting the bone morphogenetic protein (BMP) and Wnt signaling pathways with supplementation of insulin-like growth factor 1 (IGF-1) [5, 6]. We postulate that our retinal differentiation strategy can be generally applied to different types of adult stem cells
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