Metabolic stress and early cell death in photoreceptor precursor cells following retinal transplantation
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Le résumé fourni par la source
BACKGROUND: Progressive photoreceptor loss in retinal degenerative diseases leads to irreversible vision impairment. Transplantation of human embryonic or induced pluripotent stem cell-derived photoreceptor precursor cells (PRPCs) offers potential for vision restoration. However, substantial early donor cell loss remains a major challenge. This study aims to elucidate the mechanisms underlying early PRPC loss and to evaluate host retinal responses to transplantation. METHODS: PRPCs derived from human embryonic stem cells (hESC)-based retinal organoids were subretinally transplanted into both normal and degenerated canine retinas to investigate the impact of host retinal degeneration on transplant survival and integration. Single-cell RNA sequencing (scRNAseq) was performed on transplanted PRPCs 3 days post-transplantation into normal canine retinas, as well as on host retinal cells to identify molecular pathways associated with early donor cell loss. Non-invasive multimodal retinal imaging and immunohistochemical analyses were conducted to assess PRPC survival, integration, and host immune responses. RESULTS: Despite systemic immunosuppression, extensive early loss of human PRPCs occurred within the first week following xenotransplantation into both normal and degenerated canine retinas, suggesting that factors beyond immune activation contribute to donor cell loss. Transcriptomic analysis identified metabolic stress as a key driver of early donor cell death, characterized by dysregulation of mitochondrial function and oxidative phosphorylation pathways. Microglial infiltration into the donor cell mass was also observed in normal retinas, suggesting a response to donor cell stress and apoptosis. Beyond the initial phase of cell death, surviving donor cells integrated and persisted when transplanted into retinas with a partially preserved outer nuclear layer, whereas cell loss continued when intervention occurred at end-stage degeneration. CONCLUSIONS: Metabolic stress represents a critical barrier to PRPC survival following transplantation. Strategies aimed at enhancing metabolic resilience may improve transplantation outcomes. Furthermore, host retinal responses shape the transplant microenvironment, influencing donor cell survival and integration. These findings highlight the need for targeted interventions to mitigate early metabolic stress and optimize PRPC transplantation strategies for retinal degenerative diseases.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Metabolic stress and early cell death in photoreceptor precursor cells following retinal transplantation
- Date Crossref
- 25/07/2025
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Pennsylvania pays non établi dans la noticeUniversité ou école supérieure
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University of Wisconsin–Madison pays non établi dans la noticeUniversité ou école supérieure
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Smith-Kettlewell Eye Research Institute pays non établi dans la noticeOrganisation à but non lucratif
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Massachusetts Eye and Ear Infirmary pays non établi dans la noticeÉtablissement de santé
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Harvard University pays non établi dans la noticeUniversité ou école supérieure
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Massachusetts Eye Research and Surgery Institute pays non établi dans la noticeÉtablissement de santé
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Children's Hospital of Philadelphia pays non établi dans la noticeOrganisme public
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School of Veterinary Medicine Department of Clinical Sciences & Advanced Medicine pays non établi dans la noticeUniversité ou école supérieure
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University of Wisconsin-Madison Department of Ophthalmology and Visual Sciences pays non établi dans la noticeUniversité ou école supérieure
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Department of Ophthalmology pays non établi dans la noticeInstitution
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Schepens Eye Research Institute of Massachusetts Eye and Ear pays non établi dans la noticeStructure de recherche
University of Pennsylvania, University of Wisconsin–Madison et Smith-Kettlewell Eye Research Institute, avec 8 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.