SHED-Derived Exosomes Ameliorate Sjögren's Syndrome-Induced Hyposalivation by Suppressing Th1 Cell Response via the miR-29a-3p/T-bet Axis

Zhi-Hao Du; Wei-Xia Chu; Xin Peng; Li-Ling Wu; Yan Liu; Guang-Yan Yu; Chong Ding

doi:10.1021/acsami.4c16595

SHED-Derived Exosomes Ameliorate Sjögren's Syndrome-Induced Hyposalivation by Suppressing Th1 Cell Response via the miR-29a-3p/T-bet Axis

ACS Appl Mater Interfaces. 2025 Jan 13. doi: 10.1021/acsami.4c16595. Online ahead of print.

Authors

Zhi-Hao Du¹, Wei-Xia Chu^{2

3}, Xin Peng¹, Li-Ling Wu⁴, Yan Liu², Guang-Yan Yu¹, Chong Ding²

Affiliations

¹ Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China.
² Center Laboratory, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China.
³ Shanghai General Hospital, Shanghai 200080, P. R. China.
⁴ Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University School of Basic Medical Sciences, Beijing 100191, P. R. China.

PMID: 39803988
DOI: 10.1021/acsami.4c16595

Abstract

Background: Sjögren's syndrome (SS), an autoimmune disease, was characterized by sicca syndrome and systemic manifestations, presenting significant treatment challenges. Exosomes, naturally derived nanoparticles containing bioactive molecules, have garnered interest in regenerative medicine. The present study aimed to elucidate the immunoregulatory properties and mechanism of exosomes obtained from the stem cells derived from human exfoliated deciduous teeth (SHED-exos) in SS-induced sialadenitis. Methods: SHED-exo nanoparticles were injected into submandibular glands (SMGs) of 14-week-old nonobese diabetic (NOD) mice, a classic animal model of SS. At 21 weeks, the saliva flow rate (SFR) was measured. Lymphocyte proportions were examined via flow cytometry. Inflammatory cytokine levels were examined by the Quantibody mouse Th1/Th2/Th17 array and ELISA. miR-29a-3p expression and its regulatory effect on T-bet was detected using FISH and luciferase reporter gene assay, respectively. Results: SHED-exos injected into SMGs increased SFR, reduced lymphocytic infiltration, and decreased inflammatory cytokine levels in serum, SMG tissues, and saliva. Mechanistically, SHED-exos suppressed the Th1 proportion in spleen lymphocytes in NOD mice. Exosomal miR-29a-3p targeted and suppressed T-bet expression, which is a Th1-specific transcription factor. In vitro, SHED-exos (but not miR-29a-3p-inhibited exosomes) decreased the level of Th1 differentiation and IFN-γ and TNF-α production. Furthermore, SHED-exos (but not miR-29a-3p-inhibited exosomes) blocked the increase in IFN-γ and TNF-α production induced by T-bet overexpression. In vivo, miR-29a-3p-inhibited exosomes neither increase saliva secretion in NOD mice nor decrease lymphocytic infiltration, T-bet expression, and IFN-γ and TNF-α levels in SMGs. Conclusion: SHED-exos suppress Th1 cell differentiation and response through the miR-29a-3p/T-bet axis, contributing to amelioration of SS-induced hyposalivation.

Keywords: Sjögren’s syndrome; T-bet; Th1 cell; exosomes; miR-29a-3p; saliva.