![]() These three-dimensional structures may be produced through a variety of methods ( Kuwahara et al., 2015 Zhong et al., 2014), yet all share the ability to mimic key aspects of retinal morphogenesis, including laminar organization of the major retinal cell types. However, with restricted access to fetal tissue and an increasing need to complement animal models, human retinal organoids (HROs) derived from pluripotent stem cells have the potential to serve as a model system for human retinal development ( O'Hara-Wright and Gonzalez-Cordero, 2020) and disease pathogenesis ( Huang et al., 2019 Kruczek et al., 2021 Lukovic et al., 2020 Meyer et al., 2011 Parfitt et al., 2016). Study of human fetal retina over the last 50 years has provided important insights into retinal and foveal development at molecular, cellular and functional levels ( Cowan et al., 2020 Hendrickson and Drucker, 1992 Hendrickson and Zhang, 2019 Hendrickson et al., 2012 Hoshino et al., 2017 Ratnapriya et al., 2019 Sridhar et al., 2020). A better understanding of the mechanisms of synapse formation, specificity and maintenance at the OPL during human retinal development may provide insights into this synaptic plasticity. The effectiveness of therapeutic interventions such as gene and cellular therapy depends on the ability of photoreceptors to reestablish appropriate synaptic connections ( Gasparini et al., 2019 Singh et al., 2020). In some disease models, the combination of abnormal photoreceptor synaptic signaling and photoreceptor loss induces exploratory dendritic behavior in BCs, resulting in the formation of aberrant synapses with novel synaptic partners or at ectopic locations such as the ONL ( Haverkamp, 2006 Jones and Marc, 2005 Jones et al., 2012 Peng et al., 2000 Soto and Kerschensteiner, 2015). Studies in mouse models have shown that even before obvious cellular loss during the course of retinal disease, there may be structural and functional miswiring of the retinal circuits through a process of deafferentation ( D'Orazi et al., 2014 Jones and Marc, 2005 Jones et al., 2012). Genetic defects leading to dysfunction or degeneration of photoreceptors cause vision impairment in retinal disorders such as age-related macular degeneration, retinitis pigmentosa, Leber congenital amaurosis and congenital stationary night blindness ( Rattner et al., 1999). Overall, this study defines stages of human OPL development through mid-gestation and establishes HROs as a model system that recapitulates key aspects of human photoreceptor-bipolar cell synaptogenesis in vitro. ![]() Quantification of presynaptic protein localization confirmed progression from OPL-Stage 0 to 3 ( P<0.0001). By applying these OPL staging criteria to human retinal organoids (HROs) derived from human embryonic and induced pluripotent stem cells, we observed comparable maturation from OPL-Stage 0 at day 100 in culture up to OPL-Stage 3 by day 160. This was validated through quantification of increasingly precise subcellular localization of bassoon to the OPL with each stage ( P<0.0001). By studying the maturation state and spatial organization of photoreceptors, depolarizing bipolar cells and horizontal cells in the human fetal retina, we establish a pseudo-temporal staging system for OPL development that we term OPL-Stages 0 to 4. The development of the first synapse of the visual system between photoreceptors and bipolar cells in the outer plexiform layer (OPL) of the human retina is crucial for visual processing but poorly understood.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |