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The role of HMGB1 in BMSC transplantation for treating MODS in rats

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Abstract

The effect of bone marrow mesenchymal stem cells (BMSCs) in treatment for multiple organ dysfunction syndrome (MODS) remains unknown and the mechanism is still unclear. Therefore, the goal of this study is to investigate the effects of intracellular high mobility group box 1 protein (HMGB1) on BMSCs treating for MODS. The rats were given 15% blood loss plus 1 mg/kg lipopolysaccharide (LPS) via lower extremity superficial venous, then randomly allocated into four groups: sham group, MODS group, MODS plus BMSC group, MODS plus ethyl pyruvate (EP) group, MODS plus BMSCs plus EP group. Twenty-four hours later, rats in groups were sacrificed and then the blood and tissues were collected to evaluate the changes of tissue histopathology, cell apoptosis, inflammation level and organ function. The HGMB1 expression was monitored by RT-qPCR and Western blot. The expression of RAGE/TLR2/TLR4 and NF-κB at the protein levels was also assessed. BMSCs and/or EP exhibits an outstanding protective effect against LPS-induced histopathological injury by improving cell apoptosis, inflammatory response and the organ dysfunction but no effect on BMSC homing to the injury site. Moreover, BMSCs and/or EP inhibited LPS-induced upregulation of HMGB1, RAGE, TLR2 and TLR4 expression at protein levels and compromised p65 phosphorylation in the rat model of MODS. These findings suggest that HMGB1 is involved in BMSC treatment for MODS, through regulation of the TLR2, TLR4-mediated NF-κB signal pathway. It suggests that HMGB1 is an attractive potential target for the development of new therapeutic strategies for MODS.

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References

  • Al-Khafaji AH, Sharma S, Eschun G (2017) Multiple organ dysfunction syndrome in sepsis. Available at https://emedicine.medscape.com/article/169640-overview

  • Bakhtiary Z, Shahrooz R, Ahmadi A, Soltanalinejad F (2016) Ethyl pyruvate ameliorates the damage induced by cyclophosphamide on adult mice testes. Int J Fertil Steril 10:79

    PubMed  PubMed Central  CAS  Google Scholar 

  • Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, Miller L, Guetta E, Zipori D, Kedes LH (2003) Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium. Circulation 108:863–868

    Article  PubMed  Google Scholar 

  • Brun-Buisson C (2000) The epidemiology of the systemic inflammatory response. Intensive Care Med 26:S064–S074

    Article  Google Scholar 

  • Chen B, Na F, Yang H, Li R, Li M, Sun X, Hu B, Huang G, Lan J, Xu H (2017) Ethyl pyruvate alleviates radiation-induced lung injury in mice. Biomed Pharmacother 92:468–478

    Article  PubMed  CAS  Google Scholar 

  • Dong W, Cai B, Pena G, Pisarenko V, Vida G, Doucet D, Lee M, Sharpe S, Lu Q, Xu D-Z (2010) Ethyl pyruvate prevents inflammatory responses and organ damage during in porcine hemorrhage. Shock (Augusta, Ga) 34:205

    Article  CAS  Google Scholar 

  • Du XW, Wu HL, Zhu YF, Hu JB, Jin F, Lv RP, Sun S, Wang HY, Xu JW (2013) Experimental study of therapy of bone marrow mesenchymal stem cells or muscle-like cells/calcium alginate composite gel for the treatment of stress urinary incontinence. Neurourol Urodyn 32:281–286

    Article  PubMed  CAS  Google Scholar 

  • El-Menyar A, Al Thani H, Zarour A, Tuma M, AbdulRahman H, Parchani A, Peralta R, Latifi R (2013) Multiple Organ Dysfunction Syndrome (MODS): is it preventable or inevitable? Int J Clin Med 3:722

    Article  Google Scholar 

  • Erlandsson Harris H, Andersson U (2004) Mini-review: the nuclear protein HMGB1 as a proinflammatory mediator. Eur J Immunol 34:1503–1512

    Article  PubMed  CAS  Google Scholar 

  • Ge Y, Ezzell RM, Shaw Warren H (2000) Localization of endotoxin in the rat intestinal epithelium. J Infect Dis 182:873–881

    Article  PubMed  CAS  Google Scholar 

  • Hayakawa K, Pham L-DD, Arai K, Lo EH (2013) High-mobility group box 1: an amplifier of stem and progenitor cell activity after stroke. Brain Edema XV. Springer:31–38

    Google Scholar 

  • Heming Y, Maoxing Y, Jianzhong L (2000) The changes of gastric hormones in MODS rats models made of hemorrhage and endotoxin. J Traumatic Surg 2:86–88

    Google Scholar 

  • Herzog EL, Chai L, Krause DS (2003) Plasticity of marrow-derived stem cells. Blood 102:3483–3493

    Article  PubMed  CAS  Google Scholar 

  • Huang L-f, Yao Y-m, Sheng Z-y (2012) Novel insights for high mobility group box 1 protein-mediated cellular immune response in sepsis: a systemic review. World J Emerg Med 3:165–171

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ibrahim ZA, Armour CL, Phipps S, Sukkar MB (2013) RAGE and TLRs: relatives, friends or neighbours? Mol Immunol 56:739–744

    Article  PubMed  CAS  Google Scholar 

  • Kallis Y, Alison MR, Forbes SJ (2007) Bone marrow stem cells and liver disease. Gut 56:716–724

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim S-W, Lim C-M, Kim J-B, Shin J-H, Lee S, Lee M, Lee J-K (2011) Extracellular HMGB1 released by NMDA treatment confers neuronal apoptosis via RAGE-p38 MAPK/ERK signaling pathway. Neurotox Res 20:159–169

    Article  PubMed  CAS  Google Scholar 

  • Kung C-W, Lee Y-M, Cheng P-Y, Peng Y-J, Yen M-H (2011) Ethyl pyruvate reduces acute lung injury via regulation of iNOS and HO-1 expression in endotoxemic rats. J Surg Res 167:e323–e331

    Article  PubMed  CAS  Google Scholar 

  • Ling Bin CJ, Wang T-h, Pan X-h, Sun J, Liu P (2010a) Apoptotic protease activating factor-1 expression in the heart, liver and lung of rabbits with multiple organ dysfunction syndrome following bone marrow mesenchymal stem cells transplantation. J Clin Rehab Tissue Eng Res 14:4

    Google Scholar 

  • Ling Bin JC, Wang T, Pan X, Sun J (2010b) Bone marrow mesenchymal stem cells transplantation down-regulates the mRNA expression of the apoptotic factor Apaf-1 in hearts, spleens, and kidneys of rabbits with MODS. J Kunming Med Univ 31:6

    Google Scholar 

  • Manieri NA, Stappenbeck TS (2011) Mesenchymal stem cell therapy of intestinal disease: are their effects systemic or localized? Curr Opin Gastroenterol 27:119

    Article  PubMed  PubMed Central  Google Scholar 

  • Meng E, Guo Z, Wang H, Jin J, Wang J, Wang H, Wu C, Wang L (2008) High mobility group box 1 protein inhibits the proliferation of human mesenchymal stem cells and promotes their migration and differentiation along osteoblastic pathway. Stem Cells Dev 17:805–814

    Article  PubMed  CAS  Google Scholar 

  • Miyaji T, Hu X, Yuen PS, Muramatsu Y, Iyer S, Hewitt SM, Star RA (2003) Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice. Kidney Int 64:1620–1631

    Article  PubMed  CAS  Google Scholar 

  • Müller S, Ronfani L, Bianchi M (2004) Regulated expression and subcellular localization of HMGB1, a chromatin protein with a cytokine function. J Intern Med 255:332–343

    Article  PubMed  Google Scholar 

  • Orlic D, Hill JM, Arai AE (2002) Stem cells for myocardial regeneration. Circ Res 91:1092–1102

    Article  PubMed  CAS  Google Scholar 

  • Peng TC, Liao KW, Lai HL, Chao YFC, Chang FM, Harn H-J, Lee RP (2006) The physiological changes of cumulative hemorrhagic shock in conscious rats. J Biomed Sci 13:385–394

    Article  PubMed  CAS  Google Scholar 

  • Raman KG, Sappington PL, Yang R, Levy RM, Prince JM, Liu S, Watkins SK, Schmidt AM, Billiar TR, Fink MP (2006) The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock. Am J Physiol Gastrointest Liver Physiol 291:G556–G565

    Article  PubMed  CAS  Google Scholar 

  • Ramirez M (2013) Multiple organ dysfunction syndrome. Curr Probl Pediatr Adolesc Health Care 43:273–277

    Article  PubMed  Google Scholar 

  • Reis LA, Borges FT, Simoes MJ, Borges AA, Sinigaglia-Coimbra R, Schor N (2012) Bone marrow-derived mesenchymal stem cells repaired but did not prevent gentamicin-induced acute kidney injury through paracrine effects in rats. PLoS One 7:e44092

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sharma SK, Naidu G (2016) The role of danger-associated molecular patterns (DAMPs) in trauma and infections. J Thorac Dis 8:1406

    Article  PubMed  PubMed Central  Google Scholar 

  • Song Qiong LB, Sun J, Liu P (2009) Treatment of multiple organ dysfunction syndrome by administration of mesenchymal stem cells. Int J Surg 36:3

    Google Scholar 

  • Wakitani S, Okabe T, Horibe S, Mitsuoka T, Saito M, Koyama T, Nawata M, Tensho K, Kato H, Uematsu K (2011) Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med 5:146–150

    Article  PubMed  Google Scholar 

  • Yang H, Wang H, Chavan SS, Andersson U (2015) High mobility group box protein 1 (HMGB1): the prototypical endogenous danger molecule. Mol Med 21:S6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yang R, Zhu S, Tonnessen TI (2016) Ethyl pyruvate is a novel anti-inflammatory agent to treat multiple inflammatory organ injuries. J Inflamm 13:37

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the Natural Science Foundation of China (81360289) and the Applied Basic Research of Yunnan Province (Associated Special Program of Kunming Medical University) (2012FB076, 2015FB079, 2017FE468(1180)).

Author information

Author notes

  1. Guanghui Xiu and Jie Sun contributed equally to this work.

Authors and Affiliations

  1. Department of ICU, The Second People’s Hospital of Yunnan Province, 176 Qingnian Road, Wuhua District, Kunming, 650021, China

    Guanghui Xiu, Jie Sun, Xia Zhou, Ping Liu & Bin Ling

  2. Department of Obstetrics, The First People’s Hospital of Yunnan Province, Kunming, China

    Xiuling Li

  3. Department of Anesthesiology, The First People’s Hospital of Yunnan Province, Kunming, China

    Hua Jin

  4. Department of Anesthesiology, The affiliated Hospital of Binzhou Medical University, Binzhou, China

    Yichao Zhu

  5. Stem Cell Engineering Laboratory of Yunnan Province, Kunming General Hospital, Chengdu Military Command, Kunming, China

    Xinghua Pan

  6. Kunming Biological Diversity Regional Center of Instruments, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China

    Jian Li

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  1. Guanghui Xiu
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  2. Jie Sun
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  4. Hua Jin
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  10. Bin Ling
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Corresponding author

Correspondence to Bin Ling.

Ethics declarations

Rat care was in full compliance with the Guide for the Care and Use of Laboratory Animals and the use of laboratory animals in the research and all studies were approved by the Animal Ethical Committee of Kunming Medical University.

Conflict of interest

The authors declare that they have no conflicts of interest.

Electronic supplementary material

ESM 1

The identify of biomarkers in BMSCs Expression of CD90 + CD34 (B), CD44 + CD45 (C), and control by cultured cells was evaluated by flow cytometric analysis using anti-CD34, anti-CD44, anti-CD45, and anti-CD90 antibodies. Control isotype antibody is plotted in (A). Cultured cells were confirmed as BM-MSCs by their appearance in culture and by the CD44+CD90+CD34-CD45- phenotype (JPEG 72.3 kb)

High resolution (TIF 918 kb)

ESM 2

The beneficial effects of BMSCs on MODS treatment Different organ morphological changes in intestine (A and B), liver (C), kidney (D), lung (E), and spleen (F) of SD rats 24 hours after LPS-administration (1mg/kg i.v.) (40× magnification). (G) Histopathological analysis of the heart, lung, intestine, liver and kidney. M, MODS; N, Normal (JPEG 233 kb)

High resolution (TIF 6.90 mb)

ESM 3

BMSCs homed to damaged tissues Immunofluorescence staining of the heart (A), liver (B), spleen (C), lung (D), kidney (E), intestine (F), brain (G) and quadriceps (H) of SD rats 3 days after BMSCs transplantation. (JPEG 219 kb)

High resolution (TIF 7.30 mb)

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Xiu, G., Sun, J., Li, X. et al. The role of HMGB1 in BMSC transplantation for treating MODS in rats. Cell Tissue Res 373, 395–406 (2018). https://doi.org/10.1007/s00441-018-2823-0

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  • DOI: https://doi.org/10.1007/s00441-018-2823-0

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