SCF/SCFR Signaling Plays an Important Role in the Early Morphogenesis and Neurogenesis of Human Embryonic Neural Retina

Abstract

Background: The stem cell factor receptor (SCFR) has been demonstrated to be expressed in the neural retina of mice, rat, and human for decades. Previous reports indicate that SCFR correlates with glia differentiation of late retinal progenitor cells, retinal vasculogenesis, and homeostasis of the blood-retinal barrier. However, the role of SCF/SCFR signaling in the growth and development of the neural retina (NR), especially in the early embryonic stage, remains poorly understood. Methods: Human optic cup (OC) cultures were generated from human embryonic stem cells (hESCs) with SFEBq method. The angle between retinal pigment epithelium (RPE) and NR, the axial length of OC, and the length of the ciliary marginal zone (CMZ) were measured. Proliferation, mechanical dynamic, and cellular migration were assessed with BrdU labeling and quantitative immunofluorescence. Findings: We show that the SCF/SCFR signaling orchestrates invagination of the NR via regulation of symmetric cell division, cytoskeleton dynamic, and apical constriction of retinal progenitor cells in the CMZ. Furthermore, activation of SCF/SCFR signaling enhances neurogenesis in the central-most NR via accelerating the migration of immature ganglion cells. Interpretation: Our study reveals an important role of SCF/SCFR signaling in controlling ciliary marginal cellular behaviors during early morphogenesis and neurogenesis of the human embryonic NR, providing a new potential therapeutic target for human congenital eye diseases such as anophthalmia, microphthalmia, and congenital high myopia. Funding Statement: This study was supported by the National Key R&D program of China (2018YFA01017302), National Basic Research Program of China (2013CB967002) and National Natural Science Foundation of China (81873688). Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: All experiments were performed in accordance with the guidelines of the Ethics Committee of Southwest Hospital, The Army Medical University.