Ethanol Causes Cell Death and Neuronal Differentiation Defect During Initial Neurogenesis of the Neural Retina by Disrupting Calcium Signaling in Human Retinal Organoids
作者全名："Gong, Yu; Ge, Lingling; Li, Qiyou; Gong, Jing; Chen, Min; Gao, Hui; Kang, Jiahui; Yu, Ting; Li, Jiawen; Xu, Haiwei"
作者地址："[Gong, Yu; Ge, Lingling; Li, Qiyou; Gong, Jing; Chen, Min; Gao, Hui; Kang, Jiahui; Xu, Haiwei] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Southwest Eye Hosp, Chongqing 400038, Peoples R China; [Gong, Yu; Ge, Lingling; Li, Qiyou; Gong, Jing; Chen, Min; Gao, Hui; Kang, Jiahui; Xu, Haiwei] Key Lab Visual Damage & Regenerat & Restorat Chong, Chongqing, Peoples R China; [Gong, Yu; Li, Jiawen] Chongqing Med Univ, Dept Ophthalmol, Univ Town Hosp, Chongqing, Peoples R China; [Gong, Jing] Chongqing Univ, Coll Bioengn, Key Lab Biorheol Sci & Technol, Minist Educ, Chongqing 400044, Peoples R China; [Yu, Ting] 89th Hosp Peoples Liberat Army, Dept Clin Lab, Weifang, Peoples R China"
通信作者："Xu, HW (通讯作者)，Third Mil Med Univ, Army Med Univ, Southwest Hosp, Southwest Eye Hosp, Chongqing 400038, Peoples R China.; Xu, HW (通讯作者)，Key Lab Visual Damage & Regenerat & Restorat Chong, Chongqing, Peoples R China.; Li, JW (通讯作者)，Chongqing Med Univ, Dept Ophthalmol, Univ Town Hosp, Chongqing, Peoples R China."
来源：STEM CELL REVIEWS AND REPORTS
ESI学科分类：MOLECULAR BIOLOGY & GENETICS
WOS号：WOS:001052536800002
JCR分区：Q2
影响因子：4.5
年份：2023
卷号：
期号：
开始页：
结束页：
文献类型：Article; Early Access
关键词：Retinal neurogenesis; Ethanol; Human retinal organoids; Cell death; Neuron differentiation; Calcium signaling pathway
摘要："Fetal Alcohol Syndrome (FAS) affects a significant proportion, exceeding 90%, of afflicted children, leading to severe ocular aberrations such as microphthalmia and optic nerve hypoplasia. During the early stages of pregnancy, the commencement of neural retina neurogenesis represents a critical period for human eye development, concurrently exposing the developing retinal structures to the highest risk of prenatal ethanol exposure due to a lack of awareness. Despite the paramount importance of this period, the precise influence and underlying mechanisms of short-term ethanol exposure on the developmental process of the human neural retina have remained largely elusive. In this study, we utilize the human embryonic stem cells derived retinal organoids (hROs) to recapitulate the initial retinal neurogenesis and find that 1% (v/v) ethanol slows the growth of hROs by inducing robust cell death and retinal ganglion cell differentiation defect. Bulk RNA-seq analysis and two-photon microscope live calcium imaging reveal altered calcium signaling dynamics derived from ethanol-induced down-regulation of RYR1 and CACNA1S. Moreover, the calcium-binding protein RET, one of the downstream effector genes of the calcium signaling pathway, synergistically integrates ethanol and calcium signals to abort neuron differentiation and cause cell death. To sum up, our study illustrates the effect and molecular mechanism of ethanol on the initial neurogenesis of the human embryonic neural retina, providing a novel interpretation of the ocular phenotype of FAS and potentially informing preventative measures for susceptible populations."
基金机构：National Key Research and Development Program of China [2021YFA1101203]; National Natural Science Foundation of China [31930068]; General Project of Chongqing Natural Science Foundation [CSTB2022NSCQ-MSX0065]; Chongqing Medical University Program for Youth Innovation in Future Medicine [W0158]
基金资助正文："Funding This study was supported by funding from the National Key Research and Development Program of China grants 2021YFA1101203; the National Natural Science Foundation of China grants 31930068; General Project of Chongqing Natural Science Foundation CSTB2022NSCQ-MSX0065; Chongqing Medical University Program for Youth Innovation in Future Medicine W0158. The funding bodies had no role in study design, in the collection, analysis, or interpretation of data, in the writing of the report, or in the decision to submit the paper for publication."
