Stem cell secretome- and extracellular vesicle-based therapies for retinal pathologies

Abstract

Retinal vascular disorders and degenerative disorders are causes of irreversible vision loss. Many of the treatments available for them can slow the disease but cannot fix the retinal damage that has already taken place. Viable stem cell transplantation has been studied for retinal regeneration. However, increasing evidence shows that part of its biological activity could be mediated by paracrine signaling. This supports the development of acellular strategies based on stem cell secretome and extracellular vesicles (EVs). This narrative review integrates original preclinical and early clinical studies with relevant mechanistic, methodological, and translational literature on stem cell secretome- and EV-based approaches in retinal and optic nerve disorders. These preparations contain soluble trophic and immunomodulatory factors and vesicular cargo, including proteins, lipids, messenger RNAs, and microRNAs, that may modulate neuroinflammation, oxidative stress, apoptosis, glial activation, vascular dysfunction, angiogenesis, retinal pigment epithelial damage, photoreceptor loss, and retinal ganglion cell degeneration. According to preclinical studies, beneficial effects of various treatment strategies have been noted in animal models of numerous retinal diseases, such as diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration, retinal ischemia, and optic nerve injury. Approaches in bioengineering like preconditioning of parental cells, loading cargo, and modifying the surface of EVs may enhance tissue targeting and biological potency. Despite the promising results derived from preclinical studies on cell-based therapies, there exist a number of differences that limit their translation into clinical utilization. No retinal condition has an established indication for secretome- or EV-based therapy as of yet. Consequently, these strategies ought to be seen as investigational disease-modifying or adjunctive platforms, rather than as established substitutes for gene, pharmacological, or cell-based therapies.

Keywords: Stem cell secretome; Retinal degeneration; Exosomes; Regenerative medicine; Extracellular vesicles

Core Tip: Stem cell secretome and extracellular vesicles are under exploration as acellular therapeutic approaches for retinal disease. Their biological activity appears to depend largely on the transfer of trophic factors, proteins, lipids, and regulatory RNAs that can influence inflammation, oxidative stress, apoptosis, vascular homeostasis, and neuronal survival. Although the findings reported to date are encouraging, most of the available evidence remains preclinical. Before these products can enter routine retinal care, substantial work is still needed to standardize their production and characterization, define appropriate dosing, establish reliable potency assays, and assess long-term safety.