**Background**
Mesenchymal stem cells (MSCs) are a promising source for regenerative medicine due to their paracrine activity, releasing a secretome rich in cytokines, growth factors, and extracellular vesicles (EVs). The retinal secretome, primarily from retinal pigment epithelium (RPE) and Müller glia, is essential for retinal homeostasis and is dysregulated in diseases like diabetic retinopathy (DR) and age-related macular degeneration (AMD). This narrative review examines the cross-talk between MSC and retinal secretomes, focusing on shared factors and therapeutic implications.
**Methods**
The authors conducted a narrative review of the literature, summarizing in vitro and in vivo studies on MSC and retinal cell secretomes. They discuss the composition of MSC secretomes from various sources (bone marrow, adipose tissue, umbilical cord, Wharton's jelly), preconditioning strategies (hypoxia, 3D culture, cytokine priming), and the characterization of EVs. Retinal secretomes from RPE and Müller cells are described in physiological and pathological conditions. The review also covers preclinical studies using MSC secretomes in retinal disease models.
**Key Results**
- MSC secretomes contain growth factors (VEGF, SDF-1, TGF-β, IGF-1, FGF, NGF-β, HGF, G-CSF, EGF), cytokines (TNF-α, IL-1b, IL-6, IL-8), chemokines (CCL2, CCL5, CXCL12), and miRNAs (miR-210, miR-200b-3p, miR-146a, miR-27a/b, miR-122-5p, miR-206, lncRNA MALAT1).
- RPE secretome includes VEGF, TGF-β, PEDF, MMPs, NGF, FGF-1/2/5, IGF-1, BDNF, PDGF, CTGF, LEDGF, interleukins, TIMP, PIGF, angiogenin, EPO, somatostatin, and apolipoprotein A1. Under oxidative stress, VEGF secretion increases while PEDF decreases, promoting a proangiogenic microenvironment.
- Müller glia secretome contains thrombospondin-1, PEDF, IL-1b, IL-6, TNF-α, VEGF, MMP-2/9, CLU, osteopontin, and basigin. In hyperglycemia, Müller cells shift from PEDF to VEGF secretion.
- Preconditioning MSCs with hypoxia, TNF-α, or 3D culture enhances secretome therapeutic potential. For example, TNF-α-pretreated umbilical cord MSC secretome promotes macrophage M2 polarization via CCL2 and IL-6.
- In retinal disease models, MSC secretome reduces vaso-obliteration and neovascularization by restoring Sema3E levels and decreasing IL-17A. PDGF from MSCs protects retinal ganglion cells (RGCs) in glaucoma models.
- Bone marrow MSC secretome protects retinal morphology, regulates autophagy and apoptosis genes, and activates antioxidant machinery in retinal degeneration.
- Adipose MSC secretome promotes photoreceptor regeneration (increased Pax6, Chx10, S-Opsin, Nrl, Crx, GFAP) in sodium iodate-induced neurodegeneration and reduces neuroinflammation in blast injury models.
- Wharton's jelly MSC secretome induces apoptosis in RPE cells, suggesting a potential role in proliferative vitreoretinopathy.
**Clinical Implications**
The cross-talk between MSC and retinal secretomes offers a cell-free therapeutic strategy for retinal diseases. MSC secretomes can modulate inflammation, oxidative stress, and cell death, while retinal secretomes may influence MSC behavior. Challenges include standardizing secretome composition, optimizing delivery methods (e.g., intravitreal injection), and developing personalized factor combinations. Despite these hurdles, secretome-based therapies could avoid risks of cell transplantation (e.g., immunogenicity, tumorigenicity) and provide a ready-to-use biologic product. Future research should focus on characterizing specific factors and their mechanisms to translate these findings into clinical practice.