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Clinical Trial
. 2025 May 20;25(1):299.
doi: 10.1186/s12886-025-04078-9.

Efficacy of topical mesenchymal stem cell exosome in Sjögren's syndrome-related dry eye: a randomized clinical trial

Azam Habibi  1   2 , Amir Khosravi  3 , Masoud Soleimani  4 , Mahmood Nejabat  3 , Mahintaj Dara  5 , Negar Azarpira  6
Affiliations
Clinical Trial

Efficacy of topical mesenchymal stem cell exosome in Sjögren's syndrome-related dry eye: a randomized clinical trial

Azam Habibi et al. BMC Ophthalmol. .

Abstract

Background: Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disorder affecting salivary and lacrimal glands, leading to distressing ocular symptoms. Existing therapeutic approaches for SS-associated dry eye syndrome (DES) show insufficient efficacy. This study investigates the use of topical MSC-derived exosomes in primary SS-related DES.

Methods: In phase 1 and 2, triple-blinded, randomized trial, two vials of eye drops are given to each participant, one with code A and one with code B and only the supervisor knows the content of each vial. The treatment group (n = 8 eyes) received 10 µg of MSC-derived exosomes twice daily for two weeks and the control group (n = 8 eyes) received Phosphate buffered saline(PBS) for their respective eyes. Safety was assessed through ophthalmic exams, while DES assessment tests evaluated treatment effectiveness. Non-parametric tests employed to examine assumptions. The differences of ocular examination results between day 0 and month 3 were analyzed using a paired Student's t test. Measurement data that were not normally distributed are represented by the median (interquartile range), and comparisons were performed using the Wilcoxon rank-sum test.

Results: The treatment showed promising results, with significant improvements observed in various indicators such as reduced Ocular Surface Disease Index scores, increased tear secretion, lower fluorescein scores, and longer tear-film break-up time before and after treatment and between the controls and the treated groups. Our results showed a significant increase in multifunctional proteins such as Epidermal Growth Factor and thrombospondin-1 and conversely, the levels of pro-inflammatory cytokines, including interleukin-6 and Matrix metalloproteinase-9 significantly decreased in tear of participant before and after treatment and between the controls and the treated groups.

Conclusions: Our study underscores the safety and substantial therapeutic potential of using MSC-derived extracellular exosomes eye drops to treat SS-associated DES.

Trial registration: IRCT20211102052948N1 The study protocol has been approved in Iranian Registry of Clinical Trials at 2022-04-20.

Keywords: Dry eye; Exosomes; Mesenchymal stem cell; Sjögren's syndrome.

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Conflict of interest statement

Declarations. Ethics approval and consent to participants: Before their inclusion in the study, written informed consent was obtained from the WJ tissue donors and participants with SS. The trial was conducted in accordance with the guidelines for conducting clinical trials on human participants and the Declaration of Helsinki. Shiraz University of Medical Sciences Ethics Committee, Shiraz, Iran, approved the study protocol (IR.SUMS.REC.1400.852). The study protocol was also registered in the Iranian Registry of Clinical Trials (IRCT20211102052948N1) at 2022-04-20. Consent for publication: Before the participant enters the study, written informed consent was obtained from WJ tissue donors and SS participants for the publication of results that will be used in a completely confidential manner and solely for research purposes, and the participants’ identity will remain confidential within the framework of the law. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The CONSORT flow diagram shows how participants were assigned to groups and followed up during the clinical trial. CONSORT: Consolidated Standards of Reporting Trials
Fig. 2
Fig. 2
(a) Microscopic images of HWJMSCs morphology on days 7, 14, and 21. Scale bar: 300 μm. (b) Flow cytometry results for mesenchymal markers expression of CD90, CD105, and CD45. (c) Alizarin red and Oil Red O staining for osteogenic and adipogenic differentiation. HWJMSCs: Wharton’s jelly-derived mesenchymal stem cells
Fig. 3
Fig. 3
(a) TEM image of HWJMSC-derived exosomes morphology. Scale Bar: 300 nm. (b) DLS-determined size distribution of HWJMSC-derived exosomes. (c) Western blotting illustrates the expression of HWJMSC-derived exosome markers (CD9, CD63, and CD81). HWJMSCs: Wharton’s jelly-derived mesenchymal stem cells; DLS: Dynamic Light Scattering
Fig. 4
Fig. 4
Ocular surface and lacrimal function tests including (a) Redness, (b) OSDI, (c) Tear Secretion, (d) TFBUT, (e) TMT, (f) Fluorescein staining. In the statistical analysis, each eye was considered separately. The data are presented as Median [IQR] (𝑛 = 8 for each group). The symbol ∗ represents a statistically significant difference compared to the control group, while # represents a statistically significant difference compared to the baseline. TFBUT: Tear Film Break Up Time; OSDI: Ocular Surface Disease Index; TMT: Tear Meniscus Thickness
Fig. 5
Fig. 5
Hierarchical cluster analysis (HCA) using log2-transformed signals of the effect of HWJMSC-derived exosomes on eye clinical parameters. Heatmap displaying the indications present in individuals within clusters
Fig. 6
Fig. 6
Gene expression of pro- and anti-inflammatory modulators in the treatment and control groups, including (a) IL-22, (b) LTF, (c) THBS1, (d) MMP-9, (e) IL-6, and (f) EGF. In the statistical analysis, each eye was considered separately. The data are presented as Median [IQR] (𝑛 = 8 for each group). The symbol * represents P value < 0.05, and the symbol ** P value < 0.01. IL: Interleukin; LTF: lactoferrin; THBS1: thrombospondin-1; MMP-9: metalloproteinase-9; EGF: Epidermal Growth Factor
Fig. 7
Fig. 7
a Heatmap of a pairwise correlation for the gene expression profiles in tear samples. (red: high correlation; blue: low correlation). b Gene expression of the log2 fold changes mean during different time points
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