Table 1.
Results of animal studies of the application of UCB therapy to ocular diseases
| Study (year) | Design | Condition | Population (n) | Treatment | Control arm | Route | Frequency | Results |
|---|---|---|---|---|---|---|---|---|
| Zhu (2011) [10] | Prospective comparative randomized | Traumatic optic neuropathy | Mice (48) | hUCB-MSCs | Injured-only group, neurotrophic factor-treated group, and group treated with neurotrophic factor plus hUCB-MSCs | Intravitreal | Single injection | Significant improvement in fVEP testing in treated groups compared with nontreated group. hUCB and neurotrophic factor mixture achieved the best results |
| Zhao (2011) [17] | Prospective comparative randomized | ON injury | Mice (135) | hUCB-MSCs | Sham surgery group and unmanipulated mice receiving physiological saline solution | Intravitreal | Single injection | Increased RGC density, increased BDNF and GDNF mRNA expression, and improvement in pathological retinal changes in the hUCB-MSCs-treated groups |
| Chen (2013) [16] | Prospective comparative randomized | ON injury | Mice (132) | hUCB-MSCs | Phosphate-buffered saline | Intravitreal | Single injection | Decreased RGC apoptosis and increased RGC survival in the early phase following treatment. Beneficial effect declined over time |
| Jiang (2013) [15] | Prospective comparative randomized | Traumatic optic neuropathy | Mice (195) | hUCB-MSCs | Sham treatment | Intravitreal | Single injection | Ameliorated fVEP testing; increased RGC count and decreased RGC apoptosis |
| Zhang (2015) [12] | Prospective comparative randomized | ON injury | Rabbit (48) | hUCB-MSCs | Sham treatment | Intravitreal | Single injection | Decreased ultrastructural ON damage; improved biomechanical properties (increased maximum load, maximum stress, maximum strain, elastic limit load, elastic limit stress, and elastic limit strain) of ON |
| Shao (2015) [14] | Prospective comparative | Corneal endothelium deficiency | Rabbit (16) | hUCB-EPCs labeled with CD34 immunomagnetic nanoparticles | CD34 immunomagnetic nanoparticle-labeled UCB EPCS without a magnet; EDM stripping without injection of cells; unmanipulated rabbits | Intracameral injection plus magnetic attraction (cells migrate directionally) | Single injection | Treated corneas became relatively transparent, with little edema |
| Lv (2016) [13] | Prospective comparative randomized | ON injury | Rabbit (60) | hUCB-MSCs | Intravitreal BDNF | 1 × 106 hUCB-MSCs intravitreally | Single injection | Recovery of viscoelasticity of ON (increased stress relaxation and creep properties) in treated groups |
| Chung (2016) [8] | Prospective comparative | ON crush | Mice (90) | hUCB-MSCs | Sham treatment | Intraarterial | Single injection | Increased axon survival rates, increased visual function (GAP-43 upregulation), and increased oxygen availability (HIF-1α upregulation) |
| Wang (2016) [24] | Prospective comparative randomized | Oxygen-induced retinopathy | Mice (7) | hUCB-MSCs | Unmanipulated mice; phosphate-buffered saline-treated group. | Intravitreal | Single injection | Faster recovery from retinopathy and lower number of neovascular nuclei in UCB-MSCs-treated group |
| Zhang (2017) [9] | Prospective comparative randomized | Diabetic retinopathy | Mice (–) | hUCB-MSCs | Sham treatment | Intravitreal 0.2 × 106 cells in 2 μL | Single injection | Attenuation of retinal vascular dysfunction, BDNF and Thy-1 upregulation; decreased retinal vessel leakage, better visual function based on positive ERG testing |
| Mohamed (2017) [22] | Prospective comparative | Cryo-induced retinal injury | Mice (48) | hUCB-MSCs | Unmanipulated mice; intravenously treated group | Intravitreal vs intravenous injection | Single injection | Near-normal retinal structure in MSCs-treated group. Modulation of oxidant-apoptotic status: increased expression of Bcl-2, HMOX1, TXN2; downregulation of 3-NT and caspase-3. Increased bFGF |
| Dong (2017) [23] | Prospective comparative randomized | Diabetic retinopathy | Mice (60) | hUCB-MSCs | 2 μL phosphate-buffered saline | Intravitreal 2 μL | Single injection | Ameliorated retinal layer structure; reduced retinal vessel leakage |
| Reid (2017) [20] | Prospective interventional comparative | Oxygen-induced retinopathy | Mice (–) | hUCB-MSCs | Unmanipulated mice | Intravitreal vs intraarterial | Single injection | Comparable beneficial effects of intravitreal and intravascular administration routes on vascular repair. Fewer human cells observed in the retinal vasculature following systemic delivery |
| He (2018) [21] | Prospective comparative | Retinal laser injury | Mice (–) | hUCB-MSCs | Sham treatment |
Intravitreal 5 μL PBS alone, MSCs-Exos at a concentration of 50 μg/mL, and different concentrations of exosomes (Exo-L: 25 μg/mL, Exo-M: 50 μg/mL, and Exo-H: 75 μg/mL) for 8, 16, and 24 h |
Single injection | Downregulated expression of VEGF mRNA in RPE cells induced by MSC-derived exosomes in vivo and ex vivo after blue light stimulation; subsequent CNV reduction and ameliorated visual function |
| Jì (2018) [25] | Prospective comparative randomized | Ocular hypertension | Mice (54) | hUCB-MSCs | Unmanipulated mice; phosphate-buffered saline-treated group | Intravitreal | Single injection | Increased numbers of RGCs and axons and increased expression of GDNF and BDNF in hUCB-MSCs-treated groups |
| Koh (2018) [19] | Prospective interventional comparative | Retinal degeneration | Mice (–) | hUCB-MSCs plus steroids and cyclosporine A | Unmanipulated mice | Subretinal | Single or double injection | Preserved retinal synaptic connectivity and decreased Müller glial cell reactivity |
| Huang (2019) [11] | Prospective comparative | ON crush | Mice (/) | hUCB- 2D-MSCs vs hUCB- 3D-MSCs | ON exposed without crush | Intravitreal injection | Single injection | 2D-MSCs had stronger promoting effect than 3D-MSCs on RGC survival and ON axonal regeneration. Improved fVEP and sustained secretion of regeneration-stimulating factors (SCGF-β, HGF, MCP-1, IL-8, and SDF-1α). 2D-MSCs induced the activation of key neuroprotection pathways (JAK/STAT3 and MAPK/ERK) |
UCB umbilical cord blood, ON optic nerve, hUCB human umbilical cord blood, MSCs mesenchymal stem cells, RGCs retinal ganglion cells, fVEP flash visual evoked potential, SCGF-β stem cell growth factor-β, HGF hepatocyte growth factor, MCP-1 monocyte chemoattractant protein-1, SDF-1α stromal cell-derived factor, VEGF vascular endothelial growth factor, RPE retinal pigment epithelial, CNV corneal neovascularization, BDNF brain-derived neurotrophic factor, ERG electroretinogram recording, Bcl-2 B cell lymphoma (Bcl)-2 gene, HMOX heme oxygenase, TXN thioredoxin, 3-NT 3-nitrotyrosine, bFGF basic fibroblast growth factor, GAP-43 growth-associated protein-43, HIF-1α hypoxia-inducible factor-1α, hUCB-EPCs human umbilical cord blood endothelial progenitor cells, EDDM endothelium-Descemet membrane layer, GDNF glial cell line-derived neurotrophic factor