THE EFFECT OF MESENCHYMAL SECRETOME STEM CELL THERAPY TOWARD CASPASE-3 AND TNF-α EXPRESION IN HIPPOCAMPUS MICE MODEL OF SEPSIS
Abstract
Introduction: Sepsis is a global health problem that significantly increases morbidity and mortality worldwide. The inflammatory process in sepsis can cause damage, including to the hippocampus in the brain, potentially leading to brain dysfunction. Apoptosis mediated by caspase-3 and neuroinflammation exacerbated by TNF-α are the main mechanisms involved in this damage. Mesenchymal stem cells (MSCs) have the potential as a promising regenerative therapy to reduce brain damage by inhibiting apoptosis and reducing neuroinflammation. This study aims to assess the therapeutic effect of MSC secretome on hippocampus damage, measured through caspase-3 and TNF-α expression, in mice model of sepsis.
Methods: This experimental study used a post-test-only randomized controlled trial (RCT) design with a control group. Male mice of the Mus musculus Balb/C strain were divided into five groups: normal control (NC), sepsis control (SC) induced with LPS, and three treatment groups induced with LPS and given MSC secretome at doses of 150 μL, 300 μL, and 600 μL. Caspase-3 and TNF-α expression levels in the hippocampus were measured using immunohistochemistry. Statistical analysis was performed using ANOVA and Kruskal-Wallis tests, with significance considered at p < 0.05.
Results: Administration of mesenchymal stem cell secretome in the mice sepsis model did not result in a significant reduction in Caspase-3 or TNF-α levels in the hippocampus. Although Caspase-3 and TNF-α levels were lower in the treatment groups compared to the control group, the differences were not statistically significant. The greatest reduction in Caspase-3 occurred in the group receiving LPS and 600 μL secretome, but it still did not show a significant difference from the other groups (p=0.730 for Caspase-3 and p=0.135 for TNF-α).
Conclusion: Mesenchymal stem cell secretome administration reduced Caspase-3 and TNF-α levels in the hippocampus mice model of sepsis, but does not have a statistically significant impact.
Keywords
References
Baez-Jurado, E., Hidalgo-Lanussa, O., Barrera-Bailón, B., Sahebkar, A., Ashraf, G. M., Echeverria, V., & Barreto, G. E. (2019). Secretome of Mesenchymal Stem Cells and Its Potential Protective Effects on Brain Pathologies. Molecular Neurobiology, 56(10), 6902–6927. https://doi.org/10.1007/s12035-019-1570-x
Brites, D., & Fernandes, A. (2015). Neuroinflammation and depression: Microglia activation, extracellular microvesicles and microRNA dysregulation. In Frontiers in Cellular Neuroscience (Vol. 9, Issue DEC, pp. 1–20). Frontiers Media S.A. https://doi.org/10.3389/fncel.2015.00476
Curley, G. F., Hayes, M., Ansari, B., Shaw, G., Ryan, A., Barry, F., O’Brien, T., O’Toole, D., & Laffey, J. G. (2012). Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat. Thorax, 67(6), 496–501.
Czempik, P. F., Pluta, M. P., & Krzych, Ł. J. (2020). Sepsis-associated brain dysfunction: A review of current literature. In International Journal of Environmental Research and Public Health (Vol. 17, Issue 16, pp. 1–9). MDPI AG. https://doi.org/10.3390/ijerph17165852
Gama, K. B., Santos, D. S., Evangelista, A. F., Silva, D. N., de Alcântara, A. C., Dos Santos, R. R., Soares, M. B. P., & Villarreal, C. F. (2018). Conditioned Medium of Bone Marrow-Derived Mesenchymal Stromal Cells as a Therapeutic Approach to Neuropathic Pain: A Preclinical Evaluation. Stem Cells Int, 2018, 8179013.
Ngulum, M. N., Arifin, Wijaya, B. B., & Sunggoro, A. J. (2024). Pengaruh Secretome Sel Punca Mesenkimal Terhadap Tingkat Kerusakan Parenkim Hepar Ditinjau Dari Ekspresi Interleukin-6 Dan Caspase 3 Pada Mencit Model Sepsis. Universitas Sebelas Maret.
Petryk, N., & Shevchenko, O. (2020). Mesenchymal stem cells anti-inflammatory activity in rats: Proinflammatory cytokines. Journal of Inflammation Research, 13, 293–301. https://doi.org/10.2147/JIR.S256932
Purba, A. K. R., Mariana, N., Aliska, G., Wijaya, S. H., Wulandari, R. R., Hadi, U., Hamzah, Nugroho, C. W., van der Schans, J., & Postma, M. J. (2020). The burden and costs of sepsis and reimbursement of its treatment in a developing country: An observational study on focal infections in Indonesia. International Journal of Infectious Diseases, 96, 211–218. https://doi.org/10.1016/j.ijid.2020.04.075
Rababa, M., Hamad, D. B., & Hayajneh, A. A. (2022). Sepsis assessment and management in critically Ill adults: A systematic review. PLoS ONE, 17(7 July). https://doi.org/10.1371/journal.pone.0270711
Rudd, K. E., Johnson, S. C., Agesa, K. M., Shackelford, K. A., Tsoi, D., Kievlan, D. R., Colombara, D. V, Ikuta, K. S., Kissoon, N., Finfer, S., Fleischmann-Struzek, C., Machado, F. R., Reinhart, K. K., Rowan, K., Seymour, C. W., Watson, R. S., West, T. E., Marinho, F., Hay, S. I., … Naghavi, M. (2020). Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet (London, England), 395(10219), 200–211. https://doi.org/10.1016/s0140-6736(19)32989-7
Santamaria, G., Brandi, E., Vitola, P. La, Grandi, F., Ferrara, G., Pischiutta, F., Vegliante, G., Zanier, E. R., Re, F., Uccelli, A., Forloni, G., de Rosbo, N. K., & Balducci, C. (2021). Intranasal delivery of mesenchymal stem cell secretome repairs the brain of Alzheimer’s mice. Cell Death and Differentiation, 28(1), 203–218. https://doi.org/10.1038/s41418-020-0592-2
Sari, M. I. (2023). Efek Pemberian Sekretom Sel Punca Mesenkimal terhadap Ekspresi NF-kB, Kadar TNF-α, IL-6, IL-10, IL-4 dan Ekspresi PD-1, PD-L1 serta Survival Rate Tikus Model Sepsis. Universitas Sumatra Utara. https://doi.org/10.1161/CIRCRESAHA.111.243147
Savitri, L., Sandhika, W., Dwi Wahyu Widodo, A., Kesehatan, A., Kadiri, U., Patologi Anatomi, D., Airlangga, U., Mikrobiologi, D., & Soetomo Surabaya Jl Selomangleng no, R. (2019). Perbedaan Ekspresi Caspase 3 pada Limpa Tikus Model Sepsis yang Diinfeksi Escherichia coli ESBL dan dengan yang Diinfeksi Klebsiella pneumoniae Carbapenemase. Seminar Nasional Multidisiplin.
Sekino, N., Selim, M., & Shehadah, A. (2022). Sepsis-associated brain injury: underlying mechanisms and potential therapeutic strategies for acute and long-term cognitive impairments. In Journal of Neuroinflammation (Vol. 19, Issue 1). BioMed Central Ltd. https://doi.org/10.1186/s12974-022-02464-4
Sidharta, V. M. (2018). Pemanfaatan Produk Sekretom MSC dari Tali Pusat Manusia yang Dikultur dalam Kondisi Hipoksia pada Model Degenerasi Hippocampus. Universitas Gajah Mada.
Silva, A. Y. O., Amorim, É. A., Barbosa-Silva, M. C., Lima, M. N., Oliveira, H. A., Granja, M. G., Oliveira, K. S., Fagundes, P. M., Neris, R. L. S., Campos, R. M. P., Moraes, C. A., Vallochi, A. L., Rocco, P. R. M., Bozza, F. A., Castro-Faria-Neto, H. C., & Maron-Gutierrez, T. (2020). Mesenchymal Stromal Cells Protect the Blood-Brain Barrier, Reduce Astrogliosis, and Prevent Cognitive and Behavioral Alterations in Surviving Septic Mice. Critical Care Medicine, 48(4), E290–E298. https://doi.org/10.1097/CCM.0000000000004219
Sonneville, R., de Montmollin, E., Poujade, J., Garrouste-Orgeas, M., Souweine, B., Darmon, M., Mariotte, E., Argaud, L., Barbier, F., Goldgran-Toledano, D., Marcotte, G., Dumenil, A. S., Jamali, S., Lacave, G., Ruckly, S., Mourvillier, B., & Timsit, J. F. (2017). Potentially modifiable factors contributing to sepsis-associated encephalopathy. Intensive Care Medicine, 43(8), 1075–1084. https://doi.org/10.1007/s00134-017-4807-z
Sonneville, R., Verdonk, F., Rauturier, C., Klein, I. F., Wolff, M., Annane, D., Chretien, F., & Sharshar, T. (2013). Understanding brain dysfunction in sepsis. http://www.annalsofintensivecare.com/content/3/1/15
Williams, S. H., Che, X., Paulick, A., Guo, C., Lee, B., Muller, D., & et al. (2018). New York City house mice (Mus musculus) as potential reservoirs for pathogenic bacteria and antimicrobial resistance determinants. MBio, 9(2).
Zhang, K., Jiang, Y., Wang, B., Li, T., Shang, D., & Zhang, X. (2022). Mesenchymal Stem Cell Therapy: A Potential Treatment Targeting Pathological Manifestations of Traumatic Brain Injury. Oxidative Medicine and Cellular Longevity, 2022. https://doi.org/10.1155/2022/4645021
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