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. 2023 Apr 6;15(4):1167. doi: 10.3390/pharmaceutics15041167

Table 1.

MSC-derived exosomes in anterior segment diseases and glaucoma.

Disease Origin Route of Administration Results Stage Reference
Corneal wound Human corneal MSC-derived exosomes Topical
  • -

    Significantly greater healing in treated wounds

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    Re-epithelialization significantly accelerated in monolayers of confluent human corneal epithelial cells in culture (p < 0.005)

  • -

    Acceleration of murine corneal epithelial wound healing in vivo (p < 0.05)

 Preclinical trial (in vitro and in vivo mouse study) [18]
Corneal alkali injury Human placenta-derived MSC EVs Topical
  • -

    Promotion of corneal epithelial migration (dose-dependent pattern; Ki-67% increased), with significant improvement in wound healing

  • -

    Inhibition of inflammation and apoptosis (decrease in RNA levels of IL-1b, IL-8, TNF-a, NF-kB both in vitro + in vivo, IL-10 increased in vitro, decrease in Cas-8)

  • -

    Limited neovascularization and corneal hazing (decrease in MMP-2 and MMP-9, VEGF)

 Preclinical trial (in vitro and in vivo mouse study) [48]
Corneal wound Adipocyte-derived MSC-derived exosomes Topical
  • -

    Increase in growth of corneal stromal cells and reduced rate of apoptosis

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    Downregulation of MMP expression (MMP1, MMP2, MMP3, MMP9), upregulation in collagen synthesis (promotion of ECM synthesis)

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    Growth of corneal stromal cells increased in a dose-dependent manner with exosome concentration

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    Inhibit apoptosis of corneal stromal cells

 Preclinical trial (in vitro) [52]
Corneal wound Bone marrow derives MSC-exosomes Topical
  • -

    Significant promotion of corneal cell migration

  • -

    Reduced expression of MMP-2

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    Potential inhibitory effect on inflammation and neovascularisation

  • -

    Mild corneal epithelial scratch wound

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    Association between MMP-2 and angiogenesis

 Preclinical trial (in vitro, “cornea on a chip”: combination of human corneal cells and microfluidics to mimic ocular surface in vitro) [49]
Corneal wound Human umbilical cord MSC-derived exosomes combined with autophagy activator (AA) Rapamycin Topical
  • -

    Increased autophagic activity

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    50 nM Rapamycin showed positive effects in cell viability and migration acceleration

  • -

    Exo + AA better than either alone

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    Apoptosis percentage lowest in Exo + AA group, highest in Exo + AI

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    Reduced haze grade

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    Promotion of cellular proliferation

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    Samples treated with human umbilical MSC-derived exosomes alone showed increased proliferation and reduced hazing, and these effects were increased when AA was added

  • -

    Downregulation TNF-a, IL-1b, IL-6, CXCL-2 in mice

 Preclinical trial (mouse model) [51]
Corneal wound Adipose-derived MSC-derived exosomes loaded with miRNA 24-3p in thermosensitive hyaluronic acid hydrogel (THH) Topical(miRNA 24-3p was tested alone by subconjunctival injection)
  • -

    Limited post-operative corneal edema

  • -

    Recovery of normal corneal thickness but poor morphology and lack of tight junctions (miRNA 24-3p alone had healthy epithelium but abnormal thickness)

  • -

    Positive influence on corneal epithelial cell migration

 Preclinical trial (rabbit study) [58]
Corneal wound Induced pluripotent stem cell-derived MSC (iPSC-MSC) exosomes containing miR-432-5p (in a thermosensitive hydrogel for part of the study) Topical
  • -

    Accelerated closure with improved migration

  • -

    Downregulation of collagen expression in corneal stromal stem cells (with dramatic upregulation when miR-432-5p inhibitor was added)

  • -

    Downregulation of a-SMA expression and vimentin

  • -

    miR-432-5p potential effect on corneal transparency and reduced scarring

 Preclinical trial (in vitro and in vivo rat study) [57]
Corneal wound Human umbilical MSC-derived exosomes with miR-21 Topical
  • -

    Upregulation of migration and proliferation

  • -

    This upregulation was partially negated by miR-21 knockdown

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    Action through regulation of PTEN/PI3K/Akt pathway

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    Downregulation of PTEN in miR-21 treated samples

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    Posttranscriptional modification

  • -

    HCECs in culture

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    Promote healing of corneal defects in rats, more regular arrangement and compact structure

 Preclinical trial (in vitro and in vivo rat model) [50]
GVHD-associated dry eye disease Mouse bone marrow-derived MSC-derived exosomes (mouse study), human umbilical cord MSC-derived exosomes (clinical study) Topical
  • -

    miR-204 targets IL-6R to induce shift of M1 macrophages to immunosuppressive M2 phenotype

  • -

    Increased tear secretion and reduced corneal edema and hazing were seen in mouse models

  • -

    MSC-exosome treatment prevented corneal degeneration, increased the thickness of the central cornea and epithelium, restored corneal structure

  • -

    Downregulation of pro-inflammatory genes

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    Protective effect in conjunctiva and lacrimal gland

  • -

    miR-204 knockdown exacerbated DED

 Preclinical trial (2 dry eye mouse models) and clinical study (14 patients/28 eyes with GVHD) [4]
GVHD-associated DED Human umbilical MSC-derived exosomes Topical
  • -

    Estimated completion by 2023

 Clinical trial (phase II) with 27 study subjects affected by dry eye symptoms with cGVHD [67]
DED Human adipose-derived MSC-EVs Topical
  • -

    Marked decrease in desiccating stress in treated eyes

  • -

    No difference in normal eyes treated with human adipose-derived MSC-EVs, showing the safety of the treatment

  • -

    Inhibition of cell apoptosis

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    Suppression of NLRP3 activation-mediated inflammation

 Preclinical trial (mouse model) [65]
DED MSC-derived EVs Topical
  • -

    Increased tear production

  • -

    Upregulation of dendritic cells in DED, and treatment effectively reduced dendritic cell count, suppressed expression of MHC-II

  • -

    Downregulation of inflammatory cytokines

 Preclinical trial (in vitro and in vivo mouse study) [63]
DED Mouse adipose-derived MSC-derived exosomes Topical
  • -

    Preservation of goblet cells in the conjunctiva

  • -

    Reduction in apoptosis

  • -

    Suppression of inflammatory cytokines, stimulation of anti-inflammatory cytokine IL-10

  • -

    Suppression of NLRP3 inflammasome activation

 Preclinical trial (mouse model) [64]
DED Mouse MSC-derived exosomes coupled with ascorbic acid Topical
  • -

    Percentage of M2 macrophages increased by ascorbic acid, which reduces inflammation by removal of ROS, decreasing hyperosmolarity of the tear film

  • -

    Treatment that optimized the minimal corneal damage, increased thickness of the central cornea, and restoration of the stroma layer

  • -

    Significant increase in tear secretion

 Preclinical trial (mouse model) [66]
DED MSC-exosomes Topical
  • -

    Epithelium ultrastructure improved with more corneal chondriosome/desmosomes, better morphological features of microvilli

  • -

    More tear production, longer tear break-up time

 Preclinical trial (mouse model) [95]
cGVHD Human bone marrow-derived MSC-exosomes Tail vein injection
  • -

    Suppression of CD4 cells, TH17 cells

  • -

    Upregulation of IL-10-expressing cells

  • -

    Reduced pro-inflammatory cytokine production

 Preclinical study [61]
SSDE Human umbilical-derived MSC-exosomes In vitro peripheral blood mononuclear cells (PBMCs)
  • -

    Restore the balance in mi-RNA-125b-5p and miRNA-155-5p expression in CD4+ T cells

  • -

    Inhibition of T cell proliferation and activation

 Preclinical study (in vitro) [69]
SSDE Labial gland-derived MSC-exosomes Tail vein injections
  • -

    Induction of Tregs and suppression of Th17

 Preclinical study (mouse model) [70]
SSDE Olfactory ecto-MSC-exosomes Intravenous injections
  • -

    Secretion of IL-6 from olfactory ecto-MSC-exosomes and activation of myeloid-derived suppressor cells (MDSC) through Stat3 pathway

 [72]
Mucopolysaccharidosis IVA Human umbilical MSC-derived EVs
  • -

    Human umbilical MSC-EVs deliver functional GALNS enzyme to deficient cells

 Preclinical trial (in vitro) [75]
Glaucoma/optic nerve crush Bone marrow-derived MSC-exosomes Intravitreal injection, just posterior to the limbus
  • -

    Improved neuritogenesis

  • -

    Reduction of RGC loss after 21 days from 80–90% to 30% in the BMSC-exo treated sample

  • -

    Significant neuroprotection and preservation of function

  • -

    Dependency on the miRNA cargo in exosomes shown by AGO2 knockdown, with important candidates miR-21, miR-146a, miR-17-92

 Preclinical study (rat study) [77]
Glaucoma/optic nerve crush Human umbilical MSC-exosomes Intravitreal injection
  • -

    Neuroprotective effect but no axogenesis, likely due to miRNA content in different MSCs (bone marrow MSC vs. human umbilical MSC)

  • -

    Effect has shown to be related to miRNA content of exosomes through Argonaute-2 knockdown

  • -

    Activation of glial cells with the possible secretion of neurotrophins

 Preclinical trial (rat study) [30]
Glaucoma/ONC miR-21 Intravitreal injection
  • -

    Attenuation of astrocyte activation

  • -

    Excessive activation of glial cells possibly contributes to RGC degeneration

  • -

    Promotion of axogenesis and functional recovery in injured optic nerve

 Preclinical trial (rat study) [87]
Glaucoma (POAG) Bone marrow-derived MSC-exosomes
  • -

    Improved human trabecular meshwork cell viability after exposure to hydrogen peroxide

  • -

    Reduced production of iROS after exposure

  • -

    Downregulation of proinflammatory factors

  • -

    Upregulation of MMP2 and MMP3

  • -

    Potential alleviation of human trabecular meshwork cell dysfunction induced by oxidative stress

  • -

    Action through miRNA, with downregulation of miR-126-5p in the exosome group (this miRNA is upregulated in tears of glaucoma patients)

  • -

    Action of miR-3529-3p may reduce the inflammatory response to oxidative stress by acting on CXCL5

 Preclinical trial (in vitro) [91]
Glaucoma/ONC Human embryonic stem cell-MSC-EVs Tail vein injections
  • -

    Significant protection of retinal ganglion cell axons

  • -

    Suppression of cis p-tau accumulation, an early driver of tauopathy and neurodegeneration process

 Preclinical trial (mouse model) [29]
Glaucoma/ONC Human bone marrow-derived MSC-exosomes
  • -

    Priming of MSCs with TNF-a significantly increased the neuroprotective effect of the MSC-exosome treatment on rat and human retinal ganglion cells in culture

  • -

    Non-primed MSC-exosomes have a neuroprotective effect, but the effect is more muted without priming

  • -

    Priming has no effect on the division rate or secretory rate of exosomes, with a significant positive influence on neurotrophic factor expression (VEGF, HGF, IGF)

 Preclinical trial (in vitro) [80]
Glaucoma Human bone marrow MSC-derived exosomes Intravitreal injection
  • -

    Neuroprotection of retinal ganglion cells from death, with a decrease in the number of degenerating axons

 Preclinical study (mouse model) [78]
Glaucoma Human bone marrow MSC-derived exosomes Intravitreal injection
  • -

    AGO2 knockdown (depletion of miRNA) partially inhibited the positive effects of the exosome treatment

  • -

    Promotion of neuroprotection and functional preservation of retinal ganglion cells in 2 rat glaucomatous models

  • -

    No direct effect on intraocular pressure (IOP), but the potential to be used as adjunctive therapy to IOP-lowering medications

 Preclinical study (rat model) [79]
Optic nerve injury Human placenta-derived mesenchymal stem cells (hPSCs) In vitro immortalized R28 retinal precursor cells exposure
  • -

    Restored cell proliferation and mitochondrial quality control in R28-damaged cells

 Preclinical study (in vitro) [81]