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Identification and Characterization of Human Retinal Stem-Like Cells with Regenerative Potential [bulk RNA-seq]

ABSTRACT: Human retinal stem cells (hRSCs) hold great promise in regenerative medicine due to their ability to directly differentiate into retinal cells. However, the characteristics and roles of hRSCs remain ambiguous. Here, we employed single-cell multi-omics profiles of human ciliary marginal zone (CMZ) of fetal retinas and human retinal organoids (hROs). We discovered a unique cell population of human retinal stem-like cells (hRSLCs) that specifically resides in the retinal tip and non-pigmented CMZ and possess a new regenerative lineage into neural retinal cells. Analysis of single cell and spatial transcriptomes show that the hRSLCs of hRO exhibit consistent characterization of cellular and molecular functions with fetal retinas. Functionally, several transcription factors were identified involved in the regulation of stemness from single cell RNA-seq and ATAC-seq data, and deficiency of gene MECOME in hRSLCs leds to impaired homeostasis and diminished retinal regeneration. Furthermore, transplantation of hRO-derived hRSLCs into retinal degeneration mice exhibit the high potential for retinal repair and improved visual function. Our work combines single cell multi-omics and organoid technologies to identify and comprehensively characterize a promising hRSLCs population in both human fetal retinas and organoid, opening up new avenues for potential therapy in retinal regeneration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243314 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:Methods: Profiles of individual human retinal organoids (HRO) at 150, 200 and 250 days of development days were treated for 10 days with HBEGF and TNF, and compared to solvent controls (CTRL). N=6 HROs per timepoint and variable. Single-end sequencing with 30 Mio reads per sample was performed at a length of 75 bases on HiSeq2500 (Illumina). The sequence reads that passed quality filters were analyzed at the transcripts level. Results: Our data independently confirms that this protocol provides HROs with macular-like characteristics and shows low baseline variabilities for rods, cones and Müller glia. These features might be key for disease modeling, since most animal models lack a macula, and most other organoid protocols have low cone cell numbers. We found a significant reduction in the number of rod and cone photoreceptor cells after 10 days after HBEGF-TNF (HT) treatment. Specifically, some photoreceptors show pathologic changes, and some are apically displaced, with their nuclei protruding into or passing out of the retina. Histopathologic changes indicate photoreceptor extrusion of viable or dying cones and rods as a pathomechanism. Notably, photoreceptor displacement through the apical retinal border, and thus ectopy in the region of photoreceptor inner and outer segments, has been described in patients and animal models. In controls, photoreceptors were highly ordered, interspersed and interconnected with each other and with Müller glia processes, and these cell connections make up the outer limiting membrane. Upon HT, glial processes expanded in size, extended laterally along the retinal circumference, and replaced or covered photoreceptors over large areas – forming a seal-like glial scar. Taken together, HT induces photoreceptor degeneration via cell extrusion in conjunction with reactive gliosis, glial proliferation, retinal thickening/dyslamination, and glial seal-like scar formation, which reproduces a complex outer retinal atrophy. Interestingly, our transcriptome data revealed distinct gene expression patterns supporting our histological phenotype, specifically, cone and rod degeneration, reactive gliosis, glial proliferation, and photoreceptor cell extrusion. Conclusions: We show that combined application of HBEGF and TNF, two neuropathology associated factors, is sufficient to induce a complex human retinal pathology. We discovered cone and rod cell extrusion as a pathomechanism for photoreceptor degeneration and a potential interrelationship with glial pathologies. Pharmacological inhibitor experiments support this, and PIEZO1 and MAPK signaling as untapped therapeutic targets, even for complex pathologies. Thus, our model provides mechanistic access to several pathologic processes as well as pathogenic functions of inflammation and biomechanics.

Dataset Information

Identification and Characterization of Human Retinal Stem-Like Cells with Regenerative Potential [bulk RNA-seq]

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