Single-cell transcriptomics reveals maturation of transplanted stem cell–derived retinal pigment epithelial cells toward native state

Abstract

Transplantation of stem cell–derived retinal pigment epithelial (RPE) cells is considered a viable therapeutic option for age-related macular degeneration (AMD). Several landmark Phase I/II clinical trials have demonstrated safety and tolerability of RPE transplants in AMD patients, albeit with limited efficacy. Currently, there is limited understanding of how the recipient retina regulates the survival, maturation, and fate specification of transplanted RPE cells. To address this, we transplanted stem cell–derived RPE into the subretinal space of immunocompetent rabbits for 1 mo and conducted single-cell RNA sequencing analyses on the explanted RPE monolayers, compared to their age-matched in vitro counterparts. We observed an unequivocal retention of RPE identity, and a trajectory-inferred survival of all in vitro RPE populations after transplantation. Furthermore, there was a unidirectional maturation toward the native adult human RPE state in all transplanted RPE, regardless of stem cell resource. Gene regulatory network analysis suggests that tripartite transcription factors ( FOS , JUND , and MAFF ) may be specifically activated in posttransplanted RPE cells, to regulate canonical RPE signature gene expression crucial for supporting host photoreceptor function, and to regulate prosurvival genes required for transplanted RPE’s adaptation to the host subretinal microenvironment. These findings shed insights into the transcriptional landscape of RPE cells after subretinal transplantation, with important implications for cell-based therapy for AMD.

Towards Precision Ophthalmology: The Role of 3D Printing and Bioprinting in Oculoplastic Surgery, Retinal, Corneal, and Glaucoma Treatment

“…The implantation in a porcine model of retinitis pigmentosa showed no sign of inflammation, toxicity, or infection after one month. The potential for 2PP to develop clinically useful 3D cell-delivery scaffolds for the treatment of retinal diseases exists, but the extent of the research is limited as the majority of research on RPE cell transplantation involves non-3D-printed scaffolding [ 31 , 72 ].…”

Dielectrophoretic characterization of peroxidized retinal pigment epithelial cells as a model of age-related macular degeneration

“…This strategy can save photoreceptors, keep the retina's structural integrity, and eventually protect or restore eyesight. Exploiting the regeneration prospective of these cells is a significant step towards novel therapeutic approaches for retinal diseases, even as current research and clinical trials continue to improve the methods and address issues related to RPE transplantation [27], [28], [29]. One of the common approaches to deliver cells in subretinal space during transplantation is using subretinal injection of RPE cells [30].…”

Systematic transcriptomics analysis of calorie restriction and rapamycin unveils their synergistic interaction in prolonging cellular lifespan

“…Age-related diseases, often linked to dysfunctional mitotic and postmitotic cells, encompass a range of conditions [1][2][3] . These include cancer, where unchecked mitotic cell division leads to the formation of tumors 4 ; neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's disease, characterized by dysfunction and death of postmitotic neurons 5 ; cardiovascular ailments, where dysfunction in both mitotic and postmitotic cells contributes to conditions like atherosclerosis, arrhythmias, and heart failure 6 ; muscle atrophy, seen in sarcopenia, resulting from the deterioration of postmitotic muscle cells; osteoporosis, driven by age-related changes in postmitotic bone cells, leading to decreased bone density and an increased risk of fractures 7 ; diabetes, particularly Type 2 diabetes, stemming from the dysfunction of postmitotic pancreatic beta cells 8 ; age-related macular degeneration, affecting the macula in the retina and leading to vision loss, primarily involving postmitotic cells in the retina 9 ; and skin diseases, including age-related skin conditions that manifest as wrinkles, sagging, and other dermatological issues, primarily involving postmitotic skin cells 10 .…”