Secretome of Hypoxia-Preconditioned Mesenchymal Stem Cells Ameliorates Hyperglycemia in Type 2 Diabetes Mellitus Rats

Authors

  • Wita Widyaningsih Department of Postgraduate Biomedical Science, Faculty of Medicine, Universitas Islam Sultan Agung, Jawa Tengah, Indonesia
  • Agung Putra Department of Pathological Anatomy, Faculty of Medicine, Universitas Islam Sultan Agung, Jawa Tengah, Indonesia
  • Sri Priyantini Department of Paediatrics, Faculty of Medicine, Universitas Islam Sultan Agung, Jawa Tengah, Indonesia
  • Adi Muradi Muhar Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara, Sumatera Utara, Indonesia
  • Titiek Sumarawati Department of Postgraduate Biomedical Science, Faculty of Medicine, Universitas Islam Sultan Agung, Jawa Tengah, Indonesia
  • Setyo Trisnadi Department of Postgraduate Biomedical Science, Faculty of Medicine, Universitas Islam Sultan Agung, Jawa Tengah, Indonesia
  • Nur Dina Amalina Pharmaceutical Sciences Department, Faculty of Medicine, Universitas Negeri Semarang, Central Java, Indonesia
  • Iffan Alif Stem Cell and Cancer Research, Jawa Tengah, Indonesia
  • Ardi Prasetio Stem Cell and Cancer Research, Jawa Tengah, Indonesia
  • Risky Chandra Satria Irawan Stem Cell and Cancer Research, Jawa Tengah, Indonesia

DOI:

https://doi.org/10.48048/tis.2024.7278

Keywords:

T2DM, SH-MSCs, Hyperglycaemia, Insulin resistance

Abstract

          Introduction: Type 2 diabetes mellitus (T2DM) is a prevalent form of diabetes that affects 90 - 95 % of all diabetic patients. Insulin sensitizers and insulin exogenous supply could temporarily ameliorate hyperglycaemia; however, they are accompanied by side effects. As a result, new approaches are required to address insulin resistance and regenerate beta cells simultaneously. The secretome of hypoxic mesenchymal stem cells (SH-MSCs) contains various growth factors and anti-inflammatory cytokines that could potentially enhance insulin resistance and improve pancreatic function. Objectives: In this study, we performed SH-MSCs infusion to ameliorate HFD-induced hyperglycaemia in T2DM rats. Methods: We created a T2DM rat model using a combination of a high-fat diet (HFD) and streptozotocin (STZ) administration. Then, we administered SH-MSCs injection at doses of 250 and 500 µL and assessed the therapeutic effects of SH-MSCs. We also investigated the potential underlying mechanisms involved. Results: The administration of SH-MSCs improved hyperglycemia in rats with T2DM. Infusion of SH-MSCs at 500 µL dose decreased homeostatic model assessment for insulin resistance (HOMA-IR). Histological analysis revealed that injection of SH-MSCs alleviated morphological damage of pancreas. SH-MSCs administration also inhibit the level of IL-6 and promote the expression of CD163 type 2 macrophage. Conclusion: The results of our study indicate that SH-MSCs have the potential to improve hyperglycemia and exert a protective effect on T2DM rats.

HIGHLIGHTS

 

  • Administration of SH-MSCs effectively improved hyperglycemia and decreased insulin resistance in TD2M rats through modulation of IL-6 levels and promotes the expression of CD163 type 2 macrophage
  • Histological analysis demonstrated the protective effect of SH-MSCs on pancreatic morphology
  • SH-MSCs hold promise for improving hyperglycemia, insulin resistance, and providing a protective effect in TD2M

GRAPHICAL ABSTRACT

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References

Y Zheng, SH Ley and FB Hu. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat. Rev. Endocrinol. 2018; 14, 88-98.

MAB Khan, MJ Hashim, JK King, RD Govender, H Mustafa and JA Kaabi. Epidemiology of type 2 diabetes - global burden of disease and forecasted trends. J. Epidemiol. Glob. Health 2020; 10, 107-11.

U Galicia-Garcia, A Benito-Vicente, S Jebari, A Larrea-Sebal, H Siddiqi, KB Uribe, H Ostolaza and C Martín. Pathophysiology of type 2 diabetes mellitus. Int. J. Mol. Sci. 2020; 21, 6275.

A Kanwal, N Kanwar, S Bharati, P Srivastava, SP Singh and S Amar. Exploring new drug targets for type 2 diabetes: Success, challenges and opportunities. Biomedicines 2022; 10, 331.

ND Noronha, A Mizukami, C Caliári-Oliveira, JG Cominal, JL Rocha, DT Covas, K Swiech and KC Malmegrim. Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies. Stem Cell Res. Ther. 2019; 10, 131.

A Putra, I Rosdiana, DM Darlan, I Alif, F Hayuningtyas, I Wijaya, R Aryanti, FR Makarim and AD Antari. Intravenous administration is the best route of mesenchymal stem cells migration in improving liver function enzyme of acute liver failure. Folia Medica 2020; 62, 52-8.

A Putra, I Alif, N Hamra, O Santosa, AR Kustiyah, AM Muhar and K Lukman. MSC-released TGF-β regulate α-SMA expression of myofibroblast during wound healing. J. Stem Cells Regen. Med. 2020; 16, 73-9.

S Bhansali, V Kumar, UN Saikia, B Medhi, V Jha, A Bhansali and Dutta. Effect of mesenchymal stem cells transplantation on glycaemic profile & their localization in streptozotocin induced diabetic Wistar rats. Indian J. Med. Res. 2015; 142, 63-71.

DM Darlan, D Munir, NK Jusuf, A Putra, R Ikhsan and I Alif. In vitro regulation of IL-6 and TGF-ß by mesenchymal stem cells in systemic lupus erythematosus patients. Medicinski Glasnik 2020; 17, 408-13.

NF Hamra, A Putra, A Tjipta, ND Amalina and Nasihun. Hypoxia Mesenchymal stem cells accelerate wound closure improvement by controlling α-smooth muscle actin expression in the full-thickness animal model. Open Access Maced. J. Med. Sci. 2021; 9, 35-41.

NS Hwang, C Zhang, YS Hwang and S Varghese. Mesenchymal stem cell differentiation and roles in regenerative medicine. Wiley Interdiscip. Rev. Syst. Biol. Med. 2009; 1, 97-106.

Y Si, Y Zhao, H Hao, J Liu, Y Guo, Y Mu, J Shen, Y Cheng, X Fu and W Han. Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats: Identification of a novel role in improving insulin sensitivity. Diabetes 2012; 61, 1616-25.

ML Quaade, P Dhumale, SGC Steffensen, HC Beck, EB Harvald, CH Jensen, L Lund, DC Andersen and SP Sheikh. Adipose-derived stem cells from type 2 diabetic rats retain positive effects in a rat model of erectile dysfunction. Int. J. Mol. Sci. 2022; 23, 1692.

SK Yap, KL Tan, NYA Rahaman, NFS Hamid, J Ooi, YS Tor, QHD Looi, LKS Tan, CW How and JB Foo. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles ameliorated insulin resistance in type 2 diabetes mellitus rats. Pharmaceutics 2022; 14, 649.

A Utami, A Putra, JW Wibowo, ND Amalina and RC Satria. Hypoxic secretome mesenchymal stem cells inhibiting interleukin-6 expression prevent oxidative stress in type 1 diabetes mellitus. Medicinski glasnik 2023; 20, 148-55.

A Putra, A Widyatmoko, S Ibrahim, F Amansyah, F Amansyah, MA Berlian, R Retnaningsih, Z Pasongka, FE Sari and B Rachmad. Case series of the first three severe COVID-19 patients treated with the secretome of hypoxia-mesenchymal stem cells in Indonesia. F1000Research 2021; 10, 228.

KC Chao, KF Chao, YS Fu and SH Liu. Islet-like clusters derived from mesenchymal stem cells in Wharton’s Jelly of the human umbilical cord for transplantation to control type 1 diabetes. PLoS One 2008; 3, e1451.

QP Xie, H Huang, B Xu, X Dong, SL Gao, B Zhang and YL Wu. Human bone marrow mesenchymal stem cells differentiate into insulin-producing cells upon microenvironmental manipulation in vitro. Differentiation 2009; 77, 483-91.

H Sunarto, S Trisnadi, A Putra, NA Sa’dyah, A Tjipta and C Chodidjah. The role of hypoxic mesenchymal stem cells conditioned medium in increasing vascular endothelial growth factors (VEGF) levels and collagen synthesis to accelerate wound healing. Indonesian J. Cancer Chemopreve. 2020; 11, 134-43.

Z Fu, ER Gilbert and D Liu. Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr. Diabetes Rev. 2013; 9, 25-53.

Y Onishi, T Hayashi, KK Sato, T Ogihara, N Kuzuya, M Anai, K Tsukuda, EJ Boyko, WY Fujimoto and M Kikuchi. Fasting tests of insulin secretion and sensitivity predict future prediabetes in Japanese with normal glucose tolerance. J. Diabetes Investig. 2010; 1, 191-5.

GSN Rao, G Prema, G Priya, SB Arumugam, V Kirthivasan, R Saibabu and KM Cherian. Comparison between serum insulin levels and its resistance with biochemical, clinical and anthropometric parameters in South Indian children and adolescents. Indian J. Clin. Biochem. 2011; 26, 22-7.

R Nakamura, A Sene, A Santeford, A Gdoura, S Kubota, N Zapata and RS Apte. IL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis. Nat. Commun. 2015; 6, 7847.

AC Cevey, FN Penas, CDA Soto, GA Mirkin and NB Goren. IL-10/STAT3/SOCS3 axis is involved in the anti-inflammatory effect of benznidazole. Front. Immunol. 2019; 10, 1267.

A Sica and A Mantovani. Macrophage plasticity and polarization: In vivo veritas. J. Clin. Investig. 2012; 122, 787-95.

AF Cruz, R Rohban and F Esni. Macrophages in the pancreas: Villains by circumstances, not necessarily by actions. Immun. Inflamm. Dis. 2020; 8, 807-24.

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Published

2024-03-01

How to Cite

Widyaningsih, W. ., Putra, A. ., Priyantini, S. ., Muhar, A. M. ., Sumarawati, T. ., Trisnadi, S. ., Amalina, N. D. ., Alif, I. ., Prasetio, A. ., & Satria Irawan, R. C. . (2024). Secretome of Hypoxia-Preconditioned Mesenchymal Stem Cells Ameliorates Hyperglycemia in Type 2 Diabetes Mellitus Rats. Trends in Sciences, 21(5), 7278. https://doi.org/10.48048/tis.2024.7278