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Waves of cell death modulate the abundance and maturation of human retinal ganglion cells

ABSTRACT: Retinal ganglion cells (RGCs) are the projection neurons that transmit visual information from the retina to the brain via the optic nerve. A substantial proportion of RGCs are eliminated by programmed cell death during development to regulate their final number, yet how cell death impacts RGC development in human retinas remains poorly understood. Here, we characterized the timing and cell-type-specificity of cell death in human fetal retinas and retinal organoids. We identified two waves of apoptosis: an early wave targeting retinal neuronal precursors and a late wave affecting RGCs and other neurons. In addition to these two waves of apoptosis, organoids displayed a distinct wave of necrosis in the innermost core region that eliminates nearly all RGCs during long-term culture. To investigate the functions of the apoptotic waves during retinal development, we differentiated BAX/BAK double mutant organoids that are deficient for apoptosis. In these mutant organoids, RGC survival was improved, RGC neurogenesis and maturation were delayed, and RGCs were lost through a compensatory increase in necrosis. Our data suggest that the waves of developmental apoptosis promote human RGC neurogenesis and maturation. Together, our results highlight the roles of cell death in human RGC development and the challenges in retinal organoid design. Overcoming these obstacles would improve the utility of retinal organoids for modeling optic neuropathies like glaucoma

ORGANISM(S): Homo sapiens

PROVIDER: GSE305194 | GEO | 2025/11/02

REPOSITORIES: GEO

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Project description:To investigate the retinal proteins associated with primary and secondary retinal ganglion cell (RGC) degeneration and explore their molecular pathways, SWATH label-free and target-based mass spectrometry was employed to identify the proteomes in various retinal locations in response to localized optic nerve injury. Unilateral partial optic nerve transection (pONT) was performed on adult Wistar rats and their retinas were harvested at 2 weeks later. To confirm the separation of primary and secondary RGC degeneration, immunohistochemistry of RNA binding protein with multiple splicing (RBPMS) and glial fibrillary acidic protein (GFAP) was performed on retinal whole-mounts. Retinal proteomes in the temporal and nasal quadrants were evaluated with high resolution hybrid quadrupole time-of-flight mass spectrometry (QTOF-MS), and SWATH-based acquisition, and their expression was compared to the corresponding retinal quadrant in contralateral control eyes and further validated by multiple reaction monitoring mass spectrometry (MRM-MS). A total of 3641 proteins (p<0.05, FDR<1%) were quantified by SWATH-MS. Bioinformatics data analysis showed that there were 35 up-regulated and 24 down-regulated proteins in the temporal quadrant while 19 and 5 proteins were up-regulated and down-regulated, respectively, in the nasal quadrant respectively (n=4, p<0.05; fold change ≥1.4 fold or ≤0.7). Six proteins were regulated in both the temporal and the nasal quadrants including CLU, GFAP, GNG5, IRF2BPL, L1CAM and CPLX1. Linear regression analysis indicated a strong association between the data obtained by SWATH-MS and MRM-MS (temporal, R2=0.97; nasal, R2=0.96). Gene ontology analysis reveals statistically significant changes in the biological processes and cellular components of primary RGC degeneration. The majority of the significant changes in structural, signaling, and cell death proteins were associated with loss of RGCs in the area of primary RGC degeneration. The combined use of SWATH-MS and MRM-MS methods detects and quantifies regional changes of retinal protein expressions after localized injury. Future investigation with this integrated approach will significantly increase understanding of diverse processes of progressive RGC degeneration from a proteomic prospective.

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Waves of cell death modulate the abundance and maturation of human retinal ganglion cells

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