Retinal Pigment Epithelium and Microglia Transplantation in Age-related Macular Degeneration.

Abstract

Age-related macular degeneration (AMD) remains a leading cause of irreversible blindness worldwide, characterized by the progressive breakdown of the outer blood-retinal barrier, accumulation of protein and lipid deposits in the subretinal space, and the consequential degeneration of macular photoreceptors. Geographic atrophy (GA) is one of the blinding end points of AMD. While current pharmaceutical interventions can slow lesion expansion or counter choroidal neovascularization, they fail to address the most significant clinical unmet need: regeneration of damaged retinal tissue to restore vision. Regenerative medicine via stem cell transplantation offers a definitive curative approach by replacing the structural and immune framework of the outer retina. This review synthesizes current advancements in human embryonic and pluripotent stem cells platforms engineered for outer retinal reconstruction. We evaluate the differentiation, culturing, and quality validation required to generate clinical-grade, polarized RPE monolayers and homeostatic microglia-like cells. Structurally, single-cell suspensions are contrasted against bioengineered patches, scaffold-free cell sheets, and advanced cell strips, analyzing how graft configuration dictates post-transplantation integration and visual recovery while balancing procedural adverse events like cell reflux and epiretinal membrane formation. Furthermore, this review addresses the microenvironmental challenges of transplanting allogeneic constructs into an inflamed, senescent host niche. We examine CRISPR-Cas9 genome editing paradigms, including cytosine base and prime editing, designed to rectify cell-intrinsic genetic vulnerabilities such as the complement factor H (CFH) risk variant. We highlight translational applications, such as knocking out the Class II transactivator to eliminate major histocompatibility complex class II (MHC-II) expression, which successfully circumvents host T-cell immune surveillance and prevents graft rejection in non-human primates. Additionally, we analyze how engineering an inhibitor-resistant colony-stimulating factor 1 receptor (CSF1R) point mutation enables exogenously administered microglia to robustly outcompete and replace maladaptive, pro-inflammatory host microglia under selective small-molecule pressure. Finally, we discuss future directions, emphasizing multi-lineage bilayered co-transplantation models that combine genome-edited RPE patches with homeostatic microglia or retinal organoids to achieve durable synaptic repair, alongside automated artificial intelligence manufacturing pipelines. Together, these combined structural, molecular, and immune-modulating strategies represent the next clinical frontier in restoring clear central vision and achieving permanent neurovascular rescue in advanced macular degeneration.