ADSCs have been the topic of several studies in the literature that examine the potential therapeutic options for these cells in retinal diseases. Rajashekar et al. found that intravitreal injection of ADSCs in streptozotocin-induced diabetic rats correlated with fewer signs of early vascular derangement characteristic of diabetic retinopathy (DR) [77]. Safwat et al. also reported that adipose-stem-cell-derived exosomes ameliorated characteristic retinal degeneration following intraocular and subconjunctival administration among streptozotocin-induced diabetic rabbits [92].

As with any surgical procedure, ADSC implantation has been assessed for potential risks to the retina. Limoli et al. recorded no complications and an improvement in scotopic electroretinographic scores following suprachoroidal grafting of mature adipocytes and ADSCs in the stromal vascular fraction enriched with platelet-rich plasma (PRP) amongst elderly patients with non-exudative age-related macular degeneration (AMD) [93]. This group also reported objective parameters following the autologous transplantation of adipocytes, ADSCs in the SVF, and platelet-rich plasma (PRP) within the suprachoroidal space of patients with dry AMD [94]. The improved visual performance also correlated with greater retinal thickness averages. Limoli et al. reported that the suprachoroidal transplantation of autologous ADSCs reduced the progression of visual deficits in dry AMD, as shown by an improvement in best-corrected visual acuity (BCVA) and logMAR values 180 days post-treatment. A longitudinal study of visual characteristics from eight patients showed a slight improvement in the visual function of patients with degenerative macula disease following suprachoroidal ADSC implantation [95].

Genetic and tissue engineering has been hypothesized for the treatment of DR [96]. Vision loss from advanced ischemic or late (proliferative) DR is often irreversible. Therapeutic advantages are best seen with treatment during the earlier stages of DR [97]. Modern-day strategies mostly recommend hyperglycemic control (as well as the control of other vasculopathic patient-specific risk factors) during the mild and early moderate stages of non-proliferative DR. Improving glycemic control following prolonged periods of retinal exposure to hyperglycemic stress, however, can still cause non-reversible effects of previous retinal microvascular damage. Laser or intravitreal treatments are usually performed when there are signs of active DR. ADSCs have been suggested to provide protective effects against retinal ischemic damage [98] and to retinal extracellular vesicles [99].

Rajashekar et al. proposed a strategy to regenerate the retinal vasculature and neuronal cell integrity via intravitreal injection of ADSCs in streptozotocin-induced murine models of early DR [100]. ADSCs were reported to integrate into retinal perivasculature and, thus, reconstitute the blood–retinal barrier within several weeks.

It has also been postulated that the administration of autologous ADSC exosomes to streptozotocin-induced diabetic rabbits could attenuate diabetic-retinopathy-related neurodegeneration and microvasculopathy via increased microRNA-222 expression [92]. Elschaer et al. subsequently concluded that intravitreal injections of either hADSC- or adipose-SC-conditioned medium primed with cytokines yielded a reduction in vascular permeability and an improvement in electroretinogram scores [101]. ADSCs have also been found to mediate angiogenesis via paracrine mechanisms in retinal endothelial cells and promote retinal regeneration in vitro [102]. ADSC-CM and paracrine factors were associated with better visual functions post-injection in early DR Ins2Akita mouse models.

ADSCs are known to play a role in retinal and photoreceptor cell proliferation [103]. hADSCs have shown a trilineage potential to proliferate, migrate, differentiate into RPE cells when exposed to an RPE-cell-conditioned medium [104]. Yu et al. reported that adipose-derived mesenchymal stem cell exosomes ameliorated laser-induced retinal injury among mice and prevented extensive photoreceptor cell damage via the downregulation of monocyte chemotactic protein-1 [105]. Xu et al. also found that orbital ADSCs isolated via direct explant culture showed the earlier and stronger expression of markers indicating eye field and retinal photoreceptor differentiation than those generated by the conventional enzyme method [106].

Late-phase optic nerve disease yields profound functional limitations, which usually tend to be irreversible [107]. ADSCs, however, may produce a paradigm shift if viable therapies can be established. ADSCs have been reported to offer neuroprotection to retinal ganglion cells and may promote the regeneration of axons in the optic nerve head via the secretion of trophic “paracrine” factors [108]. ADSC exosomes possess bioactive molecules such as microRNAs and immunoregulatory, trophic, and growth factors, which provide pro-angiogenic effects for the possible re-vascularization of ischemic retinal or neural tissue [109]. Faber et al. suggested that ADSCs could be administered intravitreally without adverse consequences [110]. The results were based on clinical findings in a single patient with non-arteritic anterior ischemic optic neuropathy (NAION). Oner et al. reported a slight improvement in visual acuity among patients with optic atrophy following the suprachoroidal implantation of ADSCs. This patient also showed visual field and mfERG recording improvements after treatment [111].

Experiments based on in vivo ADSC transplantation have shown possible therapeutic benefits in rat models with ameliorated optic nerve injury. Treatment showed signs of inhibiting insult-induced inflammation [112,113]. The effects of ADSCs on optic nerve injuries have also been studied in Sprague Dawley rats. Experiments showed that an adipose SC concentrated conditioned medium (ASC-CCM) primed with inflammatory cytokines to induce the expression of tumor necrosis factor-stimulated protein 6 (TSG-6) improved the retinal barrier function and reduced visual deficits via neuroglial support mechanisms when injected intravitreally following mild traumatic brain injury in mice [114,115]. Jha et al. also highlighted the potential of the ADSC concentrated conditioned medium for regulating retinal neurodegeneration following mild traumatic brain injury [116].

Studies have reported that ADSC therapy could be beneficial in thyroid-associated orbitopathy [117]. It has also been suggested that insulin-like growth factor 1 has pro-adipogenic and pro-proliferative effects on ADSCs extracted from thyroid-associated ophthalmopathy patients via in vitro studies [118]. The topical prostaglandin analog bimatoprost has been reported, however, to inhibit human orbital ADSCs [119].

Wu et al. reviewed the potential of iPSCs derived from autologous adipose tissue to forge patient-specific remedies for degenerative and acquired oculoplastic diseases [120]. Lee et al. reported orbital volume augmentation following the intraorbital injection of ADSCs in rabbits [121]. The rabbits showed an increase in the exophthalmometric value of about 2.5 mm after three months. Li et al. induced autoimmune dacryoadenitis in rabbits via the intravenous infusion of activated autologous peripheral blood lymphocytes. Acute treatment using ADSCs was attributed to the reduced expression of inflammatory markers and increased basal tear volume [122].