The Effect of Hypoxic MSC Exosome on IL-10 and SOCS3 Expression

  • Siti Sundari Sundari Undergraduate Student of Biomedical Science Program, Faculty of Medicine, Sultan Agung Islamic University, Indonesia
  • Agung Putra Departement of Biomedical Science, Faculty of Medicine, Sultan Agung Islamic University, Indonesia
  • Titiek Sumarawati Stem Cell and Cancer Research (SCCR) Laboratory, Semarang, Indonesia
  • Eko Setiawan Department of Surgery, Faculty of Medicine, Sultan Agung Islamic University, Indonesia
  • Joko Wahyu Wibowo Faculty of Medicine, Sultan Agung Islamic University, Indonesia
  • Hadi Sarosa Faculty of Medicine, Sultan Agung Islamic University, Indonesia
Keywords: EH-MSCs, IL-10; SOCS3, Diabetes Mellitus, Exosomes

Abstract

Background: Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and persistent inflammation. Increased expression of Suppressor of Cytokine Signaling 3 (SOCS3) and decreased Interleukin-10 (IL-10) contribute to the progression of inflammation and impaired insulin signaling. Mesenchymal stem cell-derived exosomes under hypoxic conditions (EH-MSCs) have shown potential anti-inflammatory effects and may improve inflammatory responses in T2DM. Objective: This study aimed to determine the effect of hypoxic mesenchymal stem cell exosomes (EH-MSCs) on IL-10 and SOCS3 expression in Wistar rats with type 2 diabetes mellitus. Methods: This was an in vivo experimental study using a randomized post-test only control group design. Twenty-eight Wistar rats were divided into four groups (n=7 each): negative control (K1), positive control (K2), treatment with intravenous injection of EH-MSCs 250 µL (K3), and treatment with intravenous injection of EH-MSCs 500 µL (K4). IL-10 and SOCS3 expression levels were measured using qRT-PCR on day 30. Data were analyzed using One-Way ANOVA followed by Post Hoc LSD test with a significance level of p<0.05. Results: The mean IL-10 expression was highest in K3 (1.99 ± 0.39), followed by K4 (1.47 ± 0.49), K2 (1.37 ± 0.54), and K1 (1.12 ± 0.31), with a statistically significant difference among groups (p = 0.009). Meanwhile, the mean SOCS3 expression was highest in K1 (1.09 ± 0.41) and lowest in K3 (0.56 ± 0.11), with significant differences among groups (p = 0.018). These findings indicate that EH-MSC administration increased IL-10 expression and decreased SOCS3 expression, particularly at the 250 µL dose. Conclusion: Hypoxic mesenchymal stem cell-derived exosomes significantly increased IL-10 expression and decreased SOCS3 expression in T2DM model rats, with the 250 µL dose showing the most effective anti-inflammatory response. EH-MSCs have potential as a therapeutic strategy for reducing inflammation in T2DM.

References

Soelistijo S. Pedoman Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 Dewasa di Indonesia 2021. Global Initiative for Asthma. 2021;46.

Wahidin M, Achadi A, Besral B, Kosen S, Nadjib M, Nurwahyuni A, et al. Projection of diabetes morbidity and mortality till 2045 in Indonesia based on risk factors and NCD prevention and control programs. Sci Rep. 2024;14(1):1–17.

DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers. 2015;1(July):1–23.

Falasca M, Maffucci T, Acosta-Martinez M, Cabail MZ. The PI3K/Akt Pathway in Meta-Inflammation. International Journal of Molecular Sciences 2022, Vol 23, Page 15330 [Internet]. 2022 Dec 5 [cited 2025 May 28];23(23):15330. Available from: https://www.mdpi.com/1422-0067/23/23/15330/htm

Yadav S, Maity P. The Opportunities and Challenges of Mesenchymal Stem Cells-Derived Exosomes in Theranostics and Regenerative Medicine. 2024;1–26.

Webber S. International Diabetes Federation. Vol. 102, Diabetes Research and Clinical Practice. 2013. 147–148 p.

Dinas Kesehatan Republik Indonesia. Riset Kesehatan Dasar. Diabetes Mellitus. 2013;87–90.

Association AD. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2018. Diabetes Care [Internet]. 2018 Jan 1 [cited 2025 May 28];41(Supplement_1):S13–27. Available from: https://dx.doi.org/10.2337/dc18-S002

Tsalamandris S, Antonopoulos AS, Oikonomou E, Papamikroulis GA, Vogiatzi G, Papaioannou S, et al. The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives. European Cardiology Review [Internet]. 2019 [cited 2025 May 28];14(1):50. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6523054/

Cao L, Wang Z, Wan W. Suppressor of cytokine signaling 3: Emerging role linking central insulin resistance and Alzheimer’s disease. Front Neurosci [Internet]. 2018 Jun 20 [cited 2025 May 28];12(JUN):323321. Available from: www.frontiersin.org

Rieusset J, Bouzakri K, Chevillotte E, Ricard N, Jacquet D, Bastard JP, et al. Suppressor of Cytokine Signaling 3 Expression and Insulin Resistance in Skeletal Muscle of Obese and Type 2 Diabetic Patients. Diabetes. 2004 Sep 1;53(9):2232–41.

Novianti Y, Nur’aeny N. Exploring Interleukin-10 Levels in Diabetes Patients with and without Oral Diseases: A Systematic Review. J Inflamm Res. 2024;17(January):541–52.

Venkat P, Zacharek A, Landschoot-Ward J, Wang F, Culmone L, Chen Z, et al. Exosomes derived from bone marrow mesenchymal stem cells harvested from type two diabetes rats promotes neurorestorative effects after stroke in type two diabetes rats. Exp Neurol [Internet]. 2020 Dec 1 [cited 2025 May 16];334:113456. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0014488620302879

Tan Y, Nie W, Chen C, He X, Xu Y, Ma X, et al. Mesenchymal stem cells alleviate hypoxia-induced oxidative stress and enhance the pro-survival pathways in porcine islets. Exp Biol Med [Internet]. 2019 Jun 1 [cited 2025 May 28];244(9):781. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6567589/

Cheng P, Xie X, Hu L, Zhou W, Mi B, Xiong Y, et al. Hypoxia endothelial cells-derived exosomes facilitate diabetic wound healing through improving endothelial cell function and promoting M2 macrophages polarization. Bioact Mater [Internet]. 2023 Mar 1 [cited 2025 May 21];33:157. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10681882/

Satyadev N, Rivera MI, Nikolov NK, Fakoya AOJ. Exosomes as biomarkers and therapy in type 2 diabetes mellitus and associated complications. Front Physiol. 2023;14(September):1–21.

Chen X, Liu Z, Liu W, Wang S, Jiang R, Hu K, et al. NF-κB-Inducing Kinase Provokes Insulin Resistance in Skeletal Muscle of Obese Mice. Inflammation [Internet]. 2023 Aug 1 [cited 2025 Jul 6];46(4):1445–57. Available from: https://link.springer.com/article/10.1007/s10753-023-01820-7

Rieusset J, Bouzakri K, Chevillotte E, Ricard N, Jacquet D, Bastard JP, et al. Suppressor of Cytokine Signaling 3 Expression and Insulin Resistance in Skeletal Muscle of Obese and Type 2 Diabetic Patients. Diabetes [Internet]. 2004 Sep 1 [cited 2025 Jul 6];53(9):2232–41. Available from: https://dx.doi.org/10.2337/diabetes.53.9.2232

Carlini V, Noonan DM, Abdalalem E, Goletti D, Sansone C, Calabrone L, et al. The multifaceted nature of IL-10: regulation, role in immunological homeostasis and its relevance to cancer, COVID-19 and post-COVID conditions. Front Immunol [Internet]. 2023 [cited 2025 May 29];14:1161067. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10287165/

Liang ZY, Xu XJ, Rao J, Yang ZL, Wang CH, Chen CM. Mesenchymal Stem Cell-Derived Exosomal MiRNAs Promote M2 Macrophages Polarization: Therapeutic Opportunities for Spinal Cord Injury. Front Mol Neurosci [Internet]. 2022 Jul 12 [cited 2025 May 29];15:926928. Available from: www.frontiersin.org

Oveili E, Vafaei S, Bazavar H, Eslami Y, Mamaghanizadeh E, Yasamineh S, et al. The potential use of mesenchymal stem cells-derived exosomes as microRNAs delivery systems in different diseases. Cell Commun Signal [Internet]. 2023 Dec 1 [cited 2025 Jul 6];21(1):20. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9869323/

Wang X, Gu H, Qin D, Yang L, Huang W, Essandoh K, et al. Exosomal MIR-223 Contributes to Mesenchymal Stem Cell-Elicited Cardioprotection in Polymicrobial Sepsis. Sci Rep [Internet]. 2015 Sep 8 [cited 2025 Jul 6];5(1):1–16. Available from: https://www.nature.com/articles/srep13721

Nakano M, Kubota K, Kobayashi E, Chikenji TS, Saito Y, Konari N, et al. Bone marrow-derived mesenchymal stem cells improve cognitive impairment in an Alzheimer’s disease model by increasing the expression of microRNA-146a in hippocampus. Sci Rep [Internet]. 2020 Dec 1 [cited 2025 Jul 6];10(1):10772. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7330036/

Martin-Rufino JD, Espinosa-Lara N, Osugui L, Sanchez-Guijo F. Targeting the Immune System With Mesenchymal Stromal Cell-Derived Extracellular Vesicles: What Is the Cargo’s Mechanism of Action? Front Bioeng Biotechnol. 2019 Nov 5;7:482639.

Huang C, Li H, Zhang Z, Mou T, Wang D, Li C, et al. From Mechanism to Therapy: The Role of MSC-EVs in Alleviating Radiation-Induced Injuries. Pharmaceutics 2025, Vol 17, Page 652 [Internet]. 2025 May 16 [cited 2025 Jul 6];17(5):652. Available from: https://www.mdpi.com/1999-4923/17/5/652/htm

Liu W, Long Q, Zhang W, Zeng D, Hu B, Chen L, et al. miRNA-221-3p derived from M2-polarized tumor-associated macrophage exosomes aggravates the growth and metastasis of osteosarcoma through SOCS3/JAK2/STAT3 axis. Aging (Albany NY) [Internet]. 2021 [cited 2025 Jul 6];13(15):19760. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8386545/

Kim YE, Sung DK, Bang Y, Sung SI, Yang M, Ahn SY, et al. SOCS3 Protein Mediates the Therapeutic Efficacy of Mesenchymal Stem Cells against Acute Lung Injury. Int J Mol Sci [Internet]. 2023 May 1 [cited 2025 Jul 6];24(9):8256. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10179427/

Published
2026-04-26
How to Cite
1.
Sundari SS, Agung Putra, Titiek Sumarawati, Eko Setiawan, Joko Wahyu Wibowo, Hadi Sarosa. The Effect of Hypoxic MSC Exosome on IL-10 and SOCS3 Expression. woh [Internet]. 2026Apr.26 [cited 2026Apr.27];:212-. Available from: https://jurnal.fkmumi.ac.id/index.php/woh/article/view/2885
Section
Articles