Comparison of the Response to the CXCR4 Antagonist AMD3100 during the Development of Retinal Organoids Derived from ES Cells and Zebrafish Retina

Abstract

Retinal organoids generated from human embryonic stem cells or iPSCs recreate the key structural and functional features of mammalian retinal tissue in vitro. However, the differences in the development of retinal organoids and normal retina in vivo are not well defined. Thus, in the present study, we analyzed the development of retinal organoids and zebrafish retina after inhibition of CXCR4, a key role in neurogenesis and optic nerve development, with the antagonist AMD3100. Our data indicated that CXCR4 was mainly expressed in ganglion cells in retinal organoids and was rarely expressed in amacrine or photoreceptor cells. AMD3100 treatment reduced the retinal organoid generation ratio, impaired differentiation, and induced morphological changes. Ganglion cells, amacrine cells, and photoreceptors were decreased and abnormal locations were observed in organoids treated with AMD3100. Neuronal axon outgrowth was also damaged in retinal organoids. Similarly, a decrease of ganglion cells, amacrine cells, and photoreceptors and the distribution of neural outgrowth was induced by AMD3100 treatment in zebrafish retina. However, abnormal photoreceptor ensembles induced by AMD3100 treatment in the organoids were not detected in zebrafish retina. Therefore, our study suggests that although retinal organoids might provide a reliable model for reproducing a retinal developmental model, there is a difference between the organoids and the retina in vivo.

Inhibition of Cxcr4 Disrupts Mouse Embryonic Palatal Mesenchymal Cell Migration and Induces Cleft Palate Occurrence

“…In 2008, it was approved by the US Food and Drug Administration (FDA) and combined with granulocyte colony stimulating factor (G-CSF) as a hematopoietic stem cell mobilization agent for autologous transplantation of patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM) [ 49 ]. During embryonic development, plerixafor treatment reduced the generation rate of retinal organs, damaged the differentiation of ganglion cells and induced morphological changes [ 50 ]. Since the use of plerixafor also had an inhibitory effect on palatal development in our preliminary experiment, it was difficult to reveal the teratogenicity of plerixafor on CP occurrence when 100 mg/kg RA was used in combination with plerixafor.…”