Low-dose radiation induces unstable gene expression in developing human iPSC-derived retinal ganglion organoids

Abstract

The effects of low-dose radiation on undifferentiated cells carry important implications. However, the effects on developing retinal cells remain unclear. Here, we analyzed the gene expression characteristics of neuronal organoids containing immature human retinal cells under low-dose radiation and predicted their changes. Developing retinal cells generated from human induced pluripotent stem cells (iPSCs) were irradiated with either 30 or 180 mGy on days 4–5 of development for 24 h. Genome-wide gene expression was observed until day 35. A knowledge-based pathway analysis algorithm revealed fluctuations in Rho signaling and many other pathways. After a month, the levels of an essential transcription factor of eye development, the proportion of paired box 6 (PAX6)-positive cells, and the proportion of retinal ganglion cell (RGC)-specific transcription factor POU class 4 homeobox 2 (POU4F2)-positive cells increased with 30 mGy of irradiation. In contrast, they decreased after 180 mGy of irradiation. Activation of the “development of neurons” pathway after 180 mGy indicated the dedifferentiation and development of other neural cells. Fluctuating effects after low-dose radiation exposure suggest that developing retinal cells employ hormesis and dedifferentiation mechanisms in response to stress.

External Disruption of Ocular Development in Utero

“…In Zebrafish embryos, exposure to higher doses of radiation impacted the diameter of the eye and the inner nuclear cell layer and resulted in lens opacification [90,91]. Even exposure to low doses of radiation has been shown to interrupt human retinal ganglion cell development [92]. Limited studies in humans report similar findings, such as microphthalmia and increased risk of refractive errors [93].…”