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Tara Brooks, Yuna K Park, Anne Vielle, M. Natalia Vergara; Elucidating the Mechanisms of Developmental Cell Death in the Human Retina Using Stem Cell-derived Organoids. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3805.
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© ARVO (1962-2015); The Authors (2016-present)
The advent of stem cell technologies has opened up new opportunities for research and therapeutic development that, until recently, were unavailable. In particular, the development of human stem cell derived 3D tissues or “organoids” that mimic the native histoarchitecture, and to some degree the native functionality, have provided significant advancements in our understanding of human physiology and disease. Importantly, these retinal organoids recapitulate the spatiotemporal sequence of developmental events as they occur in vivo. In this study we take advantage of retinal organoids as a model to study the mechanisms of retinal ganglion cell death that are critical in establishing the final retinal composition during human development.
Human induced pluripotent stem cells (hiPSC) were directed to follow a neuronal lineage and were then further differentiated into 3D retinal tissue as we have previously described. Retinal organoids were collected at weekly intervals between days 42 and 78 of in vitro development and analyzed by Western blot and immunofluorescent staining for retinal ganglion cells and programmed cell death markers. Fiji software was used for quantification of confocal images.
We have characterized for the first time the timeline and extent of the first wave of retinal ganglion cell death during human development. This process seems to be guided by retinal-intrinsic cues, as it takes place even in an isolated model such as retinal organoids. Previous studies in mammals have shown that microglia-mediated phagoptosis plays a significant role in regulating ganglion cell numbers during development. Our results suggest that, in humans, there is an additional contribution to ganglion cell number regulation by programmed cell death mechanisms including caspase-dependent apoptosis.
This research has important consequences for understanding not only basic developmental processes, but also the basis of congenital retinal abnormalities that can lead to diseases of vision. Moreover, this knowledge has potential impact for translational research using retinal organoid models.
This is a 2020 ARVO Annual Meeting abstract.
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