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Bone marrow mesenchymal stem cell transplantation protects rats from myocardial infarction by regulating TXNIP/NLRP3 pathway-mediated inflammation and fibrosis

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Abstract

Background

Bone marrow mesenchymal stem cells (BMSCs) may be a promising target in the treatment of myocardial infarction (MI). However, the underlying molecular mechanisms of BMSC therapy remain unclear.

Objective

This study sought to evaluate the efficacy of direct intramyocardial transplantation of BMSCs in a mouse model of MI.

Methods

Mouse BMSCs were transfected with small interfering RNA or overexpression plasmid targeting TXNIP. The viability, proliferation, and apoptosis of BMSCs after hypoxia treatment were detected by MTT method, EdU analysis, and flow cytometry, respectively. A mouse model of MI was constructed, after which BSMCs were injected intramyocardially immediately. Cardiac ultrasound, HE staining, TUNEL staining and ELISA, IHC analysis, and Western blot were adopted to evaluate the effects of BSMC therapy on cardiac function, myocardial inflammation, and fibrosis in mice.

Results

In vitro experiments reported that ablating TXNIP increased viability and inhibited apoptosis of hypoxia-treated BMSCs while overexpressing TXNIP did the opposite. In vivo results stated that BSMCs improved cardiac function, myocardial inflammation, and fibrosis after MI, which was further improved by silencing TXNIP but reversed by overexpressing TXNIP. Meanwhile, in vivo cell tracking experiments showed that the retained BMSCs in the myocardium decreased after transplantation, and TXNIP depletion promoted the survival of BMSCs in MI mice, whereas TXNIP overexpression did the opposite.

Conclusion

In conclusion, BMSC transplantation improves cardiac function, myocardial inflammation, and fibrosis after MI by regulating the TXNIP/NLRP3 pathway.

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Availability of data and materials

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

References

  • Adluri R, Thirunavukkarasu M, Zhan L, Akita Y, Samuel S, Otani H, Ho Y, Maulik G, Maulik N (2011) Thioredoxin 1 enhances neovascularization and reduces ventricular remodeling during chronic myocardial infarction: a study using thioredoxin 1 transgenic mice. J Mol Cell Cardiol 50(1):239–247

    Article  CAS  PubMed  Google Scholar 

  • Ashur C, Frishman W (2018) Cardiosphere-derived cells and ischemic heart failure. Cardiol Rev 26(1):8–21

    Article  PubMed  Google Scholar 

  • Chen W (2023) TGF-β regulation of T cells. Annu Rev Immunol 26(41):483–512

    Article  Google Scholar 

  • Chen W, Wang S, Xia J, Huang Z, Tu X, Shen Z (2016) Protein phosphatase 2A plays an important role in migration of bone marrow stroma cells. Mol Cell Biochem 412:173–180

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Zhao Y, Chen W, Xie L, Zhao Z, Yang J, Chen Y, Lei W, Shen Z (2017) MicroRNA-133 overexpression promotes the therapeutic efficacy of mesenchymal stem cells on acute myocardial infarction. Stem Cell Res Ther 8(1):268

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen F, Liang P, Ye F, Hou C, Pi L (2020) Mesenchymal stem cell therapy for patients with ischemic heart failure -past, present, and future. Curr Stem Cell Res Therapy. 2021;16(5):608–621

  • Dai Y, Wang S, Chang S, Ren D, Shali S, Li C, Yang H, Huang Z, Ge J (2020) M2 macrophage-derived exosomes carry microRNA-148a to alleviate myocardial ischemia/reperfusion injury via inhibiting TXNIP and the TLR4/NF-κB/NLRP3 inflammasome signaling pathway. J Mol Cell Cardiol 142:65–79

    Article  CAS  PubMed  Google Scholar 

  • Du W, Sang Y, Bai YH (2022) LRG1 expression reduced inflammation of sepsis-renal injury via activation of NLRP3 inflammasome by HIF-1 alpha. Mol Cell Toxicol 18:419–429

    Article  CAS  Google Scholar 

  • Gerbaud E, Elbaz M, Lattuca B (2020) New insights into cardiogenic shock and coronary revascularization after acute myocardial infarction. Arch Cardiovasc Dis 113(4):276–284

    Article  PubMed  Google Scholar 

  • Gibb AA, Lazaropoulos MP, Elrod JW (2020) Myofibroblasts and fibrosis: mitochondrial and metabolic control of cellular differentiation. Circ Res 127(3):427–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gnecchi M, Melo L (2009) Bone marrow-derived mesenchymal stem cells: isolation, expansion, characterization, viral transduction, and production of conditioned medium. Methods Mol Biol (Clifton, NJ) 482:281–294

    Article  CAS  Google Scholar 

  • Guo L, Du J, Yuan D, Zhang Y, Zhang S, Zhang H, Mi J, Ning Y, Chen M, Wen D et al (2020) Optimal HO preconditioning to improve bone marrow mesenchymal stem cells’ engraftment in wound healing. Stem Cell Res Ther 11(1):434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han Y, Xu X, Tang C, Gao P, Chen X, Xiong X, Yang M, Yang S, Zhu X, Yuan S et al (2018) Reactive oxygen species promote tubular injury in diabetic nephropathy: the role of the mitochondrial ros-txnip-nlrp3 biological axis. Redox Biol 16:32–46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Isaka Y (2018) Targeting TGF-β signaling in kidney fibrosis. Int J Mol Sci 19(9):2532

    Article  PubMed  PubMed Central  Google Scholar 

  • Isomi M, Sadahiro T, Ieda M (2019) Progress and challenge of cardiac regeneration to treat heart failure. J Cardiol 73(2):97–101

    Article  PubMed  Google Scholar 

  • Jackson A, Rahman G, Yin K, Long S (2021) Enhancing matured stem-cardiac cell generation and transplantation: a novel strategy for heart failure therapy. J Cardiovasc Transl Res 14(3):556–572

    Article  PubMed  Google Scholar 

  • Jang K, Tu T, Rosenblatt R, Burks S, Frank J (2020) MR-guided pulsed focused ultrasound improves mesenchymal stromal cell homing to the myocardium. J Cell Mol Med 24(22):13278–13288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji L, Long X, Tian H, Liu Y (2013) Effect of transplantation of bone marrow stem cells on myocardial infarction size in a rabbit model. World J Emerg Med 4(4):304–310

    Article  PubMed  PubMed Central  Google Scholar 

  • Jiang L, Yang A, Li X, Liu K, Tan J (2021) Down-regulation of VCAM-1 in bone mesenchymal stem cells reduces inflammatory responses and apoptosis to improve cardiac function in rat with myocardial infarction. Int Immunopharmacol 101:108180

    Article  CAS  PubMed  Google Scholar 

  • Ju X, Xue D, Wang T, Ge B, Zhang Y, Li Z (2018) Catalpol promotes the survival and VEGF secretion of bone marrow-derived stem cells and their role in myocardial repair after myocardial infarction in rats. Cardiovasc Toxicol 18(5):471–481

    Article  CAS  PubMed  Google Scholar 

  • Kim S, Cho J, Lee Y, Lee J, Kim S, Kim M, Lee M, Kang W, Lee K, Ahn Y et al (2018) Improvement in left ventricular function with intracoronary mesenchymal stem cell therapy in a patient with anterior wall st-segment elevation myocardial infarction. Cardiovasc Drugs Ther 32(4):329–338

    Article  PubMed  PubMed Central  Google Scholar 

  • Ko I, Kim B (2008) Mesenchymal stem cells for treatment of myocardial infarction. Inte J Stem Cells 1(1):49–54

    Article  CAS  Google Scholar 

  • Koitabashi N, Kass D (2011) Reverse remodeling in heart failure–mechanisms and therapeutic opportunities. Nat Rev Cardiol 9(3):147–157

    Article  PubMed  Google Scholar 

  • Koyani CN, Plastira I, Sourij H, Hallström S, Schmidt A, Rainer PP, Bugger H, Frank S, Malle E, von Lewinski D (2020) Empagliflozin protects heart from inflammation and energy depletion via AMPK activation. Pharmacol Res 158:104870

    Article  CAS  PubMed  Google Scholar 

  • Ling X, Wu W, Fan C, Xu C, Liao J, Rich L, Huang R, Repasky E, Wang X, Li F (2018) An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer. J Exp Clin Cancer Res 37(1):240

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu J, Ling B (2015) Bone marrow-derived mesenchymal stem cells in the treatment of myocardial infarction. Zhongguo Yi Xue Ke Xue Yuan Xue Bao Acta Academiae Medicinae Sinicae 37(1):108–112

    PubMed  Google Scholar 

  • Mack M (2018) Inflammation and fibrosis. Matrix Biol 68–69:106–121

    Article  PubMed  Google Scholar 

  • McMurray J, Pfeffer M (2005) Heart failure. Lancet (London, England) 365(9474):1877–1889

    Article  PubMed  Google Scholar 

  • Miao C, Lei M, Hu W, Han S, Wang Q (2017) A brief review: the therapeutic potential of bone marrow mesenchymal stem cells in myocardial infarction. Stem Cell Res Ther 8(1):242

    Article  PubMed  PubMed Central  Google Scholar 

  • Morikawa M, Derynck R, Miyazono K (2016) TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol 8(5):a021873

    Article  PubMed  PubMed Central  Google Scholar 

  • Narita T, Suzuki K (2015) Bone marrow-derived mesenchymal stem cells for the treatment of heart failure. Heart Fail Rev 20(1):53–68

    Article  CAS  PubMed  Google Scholar 

  • Orlic D, Kajstura J, Chimenti S, Bodine D, Leri A, Anversa P (2003) Bone marrow stem cells regenerate infarcted myocardium. 2003:7 Suppl 3:86–88

  • Qiu H, Liu W, Lan T, Pan W, Chen X, Wu H, Xu D (2018) Salvianolate reduces atrial fibrillation through suppressing atrial interstitial fibrosis by inhibiting TGF-β1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathways in post-MI rats. Phytomedicine: Int J Phytotherapy Phytopharmacol 51:255–265

    Article  CAS  Google Scholar 

  • Sano M, Komiyama H, Shinoda R, Ozawa R, Watanabe H, Karasawa T, Takahashi M, Torii Y, Iwata H, Kuwayama T et al (2022) NLRP3 inflammasome is involved in testicular inflammation induced by lipopolysaccharide in mice. Am J Reproduct Immunol. 2022 Apr;87(4):e13527

  • Selvaraju V, Suresh S, Thirunavukkarasu M, Mannu J, Foye J, Mathur P, Palesty J, Sanchez J, McFadden D, Maulik N (2017) Regulation of A-kinase-anchoring protein 12 by heat shock protein A12B to prevent ventricular dysfunction following acute myocardial infarction in diabetic rats. J Cardiovasc Transl Res 10(2):209–220

    Article  PubMed  Google Scholar 

  • Su H, Ji L, Xing W, Zhang W, Zhou H, Qian X, Wang X, Gao F, Sun X, Zhang H (2013) Acute hyperglycaemia enhances oxidative stress and aggravates myocardial ischaemia/reperfusion injury: role of thioredoxin-interacting protein. J Cell Mol Med 17(1):181–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun D, Huang J, Zhang Z, Gao H, Li J, Shen M, Cao F, Wang H (2012) Luteolin limits infarct size and improves cardiac function after myocardium ischemia/reperfusion injury in diabetic rats. PLoS ONE 7(3):e33491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun Y, Xu H, Tan B, Yi Q, Liu H, Tian J, Zhu J (2023) Andrographolide-treated bone marrow mesenchymal stem cells-derived conditioned medium protects cardiomyocytes from injury by metabolic remodeling. Mol Biol Rep 50(3):2651–2662

    Article  CAS  PubMed  Google Scholar 

  • Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z (2015) Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 37(6):2415–2424

    Article  CAS  Google Scholar 

  • Yue Y, Zong L, Chen Y, Feng Y, Tang N, Xu J, Zhao H (2021) Ling M Liver kinase B1 (LKB1) reduced inflammation and oxidative stress by regulating the AMPK/NLRP3 signaling pathway in LPS-induced lung injury. Mol Cell Toxicol 17:385–395

    Article  CAS  Google Scholar 

  • Zhang Z, Li S, Cui M, Gao X, Sun D, Qin X, Narsinh K, Li C, Jia H, Li C et al (2013) Rosuvastatin enhances the therapeutic efficacy of adipose-derived mesenchymal stem cells for myocardial infarction via PI3K/Akt and MEK/ERK pathways. Basic Res Cardiol 108(2):333

    Article  PubMed  Google Scholar 

  • Zhao J, Liu X, Kong F, Qi T, Cheng G, Wang J, Sun C, Luan Y (2014) Bone marrow mesenchymal stem cells improve myocardial function in a swine model of acute myocardial infarction. Mol Med Rep 10(3):1448–1454

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Cardiology, Daqing People’s Hospital, No. 213, Jianshe Road, Daqing City, 163711, Heilongjiang Province, China

    JianNan Bai, Cong Wang, HongQiang Yu, QingChao Wang, JinFeng Zhang, DanDan Shao, ZhiQiang Yu, Bo Meng & You Li

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  1. JianNan Bai
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  2. Cong Wang
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  3. HongQiang Yu
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  4. QingChao Wang
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Contributions

JB, CW, and HY designed the research study. QW performed the research. JZ provided help and advice on the experiments. DS analyzed the data. ZY, BM, and YL wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

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Correspondence to JianNan Bai.

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Conflict of interest

JianNan Bai, Cong Wang, HongQiang Yu, QingChao Wang, JinFeng Zhang, DanDan Shao, ZhiQiang Yu, Bo Meng, and You Li have no conflicts of interest to declare.

Ethical approval

The present study was approved by Daqing People's Hospital and all procedures complied with the National Institutes of Health Guide for the Use of Laboratory Animals.

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Bai, J., Wang, C., Yu, H. et al. Bone marrow mesenchymal stem cell transplantation protects rats from myocardial infarction by regulating TXNIP/NLRP3 pathway-mediated inflammation and fibrosis. Mol. Cell. Toxicol. (2024). https://doi.org/10.1007/s13273-023-00422-6

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