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Current Molecular Medicine


ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Systematic Review Article

Protein Phosphorylation Mechanism of Mesenchymal Stem Cells in the Treatment of Sepsis: A Systematic Review and Meta-analysis

Author(s): Hongwu Wang, Junlin Luo, Yong Zhong* and Lian Ma*

Volume 23, Issue 10, 2023

Published on: 23 November, 2022

Page: [1087 - 1094] Pages: 8

DOI: 10.2174/1566524023666221020124204

Price: $65


Background: The severity and mortality of sepsis are related to excessive inflammation and cytokine storm. Nevertheless, little is known about why sepsis has a significant increase in proinflammatory cytokine production, which leads to more severe inflammatory damage.

Methods: Mesenchymal stem cells have achieved certain results in the treatment of sepsis, but the specific mechanism remains to be further clarified.

Results: Therefore, this paper will elaborate on the currently recognized mechanism of mesenchymal stem cells in the treatment of sepsis, the protein phosphorylation mechanism of sepsis inflammatory response, and the possibility that mesenchymal stem cells may block the occurrence and development of sepsis by regulating relevant pathways or protein phosphorylation.

Conclusion: It provides a novel target for mesenchymal stem cells to prevent intervention or therapeutically block the development of sepsis.

Keywords: Mesenchymal, stem cell, sepsis, protein, phosphorylation, mechanism, systemic review.

Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315(8): 801-10.
[] [PMID: 26903338]
Marchant A, Goldman M, Devière J, Byl B, Vincent JL, Groote DD. Interleukin-10 production during septicaemia. Lancet 1994; 343(8899): 707-8.
[] [PMID: 7907683]
Delano MJ, Ward PA. The immune system’s role in sepsis progression, resolution, and long-term outcome. Immunol Rev 2016; 274(1): 330-53.
[] [PMID: 27782333]
Fleischmann C, Scherag A, Adhikari NKJ, et al. Assessment of global incidence and mortality of hospital-treated sepsis. Cur-rent estimates and limitations. Am J Respir Crit Care Med 2016; 193(3): 259-72.
[] [PMID: 26414292]
Zhou Y, Hu Q, Chen F, et al. Human umbilical cord matrix-derived stem cells exert trophic effects on β-cell survival in diabetic rats and isolated islets. Dis Model Mech 2015; 8(12): dmm.021857.
[] [PMID: 26398949]
Tang Q, Chen Q, Lai X, et al. Malignant transformation potentials of human umbilical cord mesenchymal stem cells both spon-taneously and via 3-methycholanthrene induction. PLoS One 2013; 8(12): e81844.
[] [PMID: 24339974]
Leng Z, Zhu R, Hou W, et al. Transplantation of ACE2- mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis 2020; 11(2): 216-28.
[] [PMID: 32257537]
He X, Ai S, Guo W, et al. Umbilical cord-derived mesenchymal stem (stromal) cells for treatment of severe sepsis: aphase 1 clinical trial. Transl Res 2018; 199: 52-61.
[] [PMID: 30044959]
Hashemian SMR, Aliannejad R, Zarrabi M, et al. Mesenchymal stem cells derived from perinatal tissues for treatment of critical-ly ill COVID-19-induced ARDS patients: a case series. Stem Cell Res Ther 2021; 12(1): 91.
[] [PMID: 33514427]
Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339(7): b2700.
[] [PMID: 19622552]
Jayaramayya K, Mahalaxmi I, Subramaniam MD, et al. Immunomodulatory effect of mesenchymal stem cells and mesenchymal stem-cell-derived exosomes for COVID-19 treatment. BMB Rep 2020; 53(8): 400-12.
[] [PMID: 32731913]
Ayala-Cuellar AP, Kang JH, Jeung EB, Choi KC. Roles of mesenchymal stem cells in tissue regeneration and immunomodula-tion. Biomol Ther 2019; 27(1): 25-33.
[] [PMID: 29902862]
Wang H, Qiu X, Ni P, et al. Immunological characteristics of human umbilical cord mesenchymal stem cells and the therapeutic effects of their transplantion on hyperglycemia in diabetic rats. Int J Mol Med 2014; 33(2): 263-70.
[] [PMID: 24297321]
Zhu R, Yan T, Feng Y, et al. Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immuno-modulatory mechanisms. Cell Res 2021; 31(12): 1244-62.
[] [PMID: 34702946]
Cho Y, Mitchell R, Paudel S, Feltham T, Schon L, Zhang Z. Compromised antibacterial function of multipotent stromal cells in diabetes. Stem Cells Dev 2019; 28(4): 268-77.
[] [PMID: 30572796]
Maldonado M, Huang T, Yang L, Xu L, Ma L. Human umbilical cord Wharton jelly cells promote extra-pancreatic insulin for-mation and repair of renal damage in STZ-induced diabetic mice. Cell Commun Signal 2017; 15(1): 43.
[] [PMID: 29041943]
Lee JW, Fang X, Gupta N, Serikov V, Matthay MA. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci 2009; 106(38): 16357-62.
[] [PMID: 19721001]
Lee JW, Fang X, Krasnodembskaya A, Howard JP, Matthay MA. Concise review: Mesenchymal stem cells for acute lung injury: role of paracrine soluble factors. Stem Cells 2011; 29(6): 913-9.
[] [PMID: 21506195]
Fang X, Neyrinck AP, Matthay MA, Lee JW. Allogeneic human mesenchymal stem cells restore epithelial protein permeability in cultured human alveolar type II cells by secretion of angiopoietin-1. J Biol Chem 2010; 285(34): 26211-22.
[] [PMID: 20554518]
Ito H, Uchida T, Makita K. Interactions between rat alveolar epithelial cells and bone marrow-derived mesenchymal stem cells: an in vitro co-culture model. Intensive Care Med Exp 2015; 3(1): 15.
[] [PMID: 26215817]
Singleton PA, Salgia R, Moreno-Vinasco L, et al. CD44 regulates hepatocyte growth factor-mediated vascular integrity. Role of c-Met, Tiam1/Rac1, dynamin 2, and cortactin. J Biol Chem 2007; 282(42): 30643-57.
[] [PMID: 17702746]
Lu H, Cook T, Poirier C, et al. Pulmonary retention of adipose stromal cells following intravenous delivery is markedly altered in the presence of ARDS. Cell Transplant 2016; 25(9): 1635-43.
[] [PMID: 26609693]
Pieroni L, Iavarone F, Olianas A, et al. Enrichments of post‐translational modifications in proteomic studies. J Sep Sci 2020; 43(1): 313-36.
[] [PMID: 31631532]
Humphrey SJ, James DE, Mann M. Protein phosphorylation: a major switch mechanism for metabolic regulation. Trends Endocrinol Metab 2015; 26(12): 676-87.
[] [PMID: 26498855]
Ren X, Han L, Li Y, et al. Isorhamnetin attenuates TNF ‐α‐induced inflammation, proliferation, and migration in human bron-chial epithelial cells via MAPK and NF‐κB pathways. Anat Rec 2021; 304(4): 901-13.
[] [PMID: 32865318]
Li C, Yu L, Mai C, Mu T, Zeng Y. KLF4 down‐regulation resulting from TLR4 promotion of ERK1/2 phosphorylation underpins inflammatory response in sepsis. J Cell Mol Med 2021; 25(4): 2013-24.
[] [PMID: 33369167]
Ziegler S, Gartner K, Scheuermann U, et al. Ca 2+ -related signaling events influence TLR9-induced IL-10 secretion in human B cells. Eur J Immunol 2014; 44(5): 1285-98.
[] [PMID: 24470136]
Zhang W, Sun Q, Gao X, Jiang Y, Li R, Ye J. Anti-inflammation of spirocyclopiperazinium salt compound LXM-10 targeting α7 nAChR and M4 mAChR and inhibiting JAK2/STAT3 pathway in rats. PLoS One 2013; 8(6): e66895.
[] [PMID: 23840548]
Dong R, Xue Z, Fan G, et al. Pin1 Promotes NLRP3 Inflammasome Activation by Phosphorylation of p38 MAPK Pathway in Sep-tic Shock. Front Immunol 2021; 12: 620238.
[] [PMID: 33717117]
Soroush F, Zhang T, King DJ, et al. A novel microfluidic assay reveals a key role for protein kinase C δ in regulating human neutrophil–endothelium interaction. J Leukoc Biol 2016; 100(5): 1027-35.
[] [PMID: 27190303]
Venet F, Foray AP, Villars-Méchin A, et al. IL-7 restores lymphocyte functions in septic patients. J Immunol 2012; 189(10): 5073-81.
[] [PMID: 23053510]
Rak-Mardyla A, Gregoraszczuk EL. ERK 1/2 and PI-3 kinase pathways as a potential mechanism of ghrelin action on cell pro-liferation and apoptosis in the porcine ovarian follicular cells. J Physiol Pharmacol 2010; 61(4): 451-8.
[PMID: 20814073]
Sepúlveda M, Burgos JI, Ciocci Pardo A, González Arbelaez L, Mosca S, Vila Petroff M. CaMKII‐dependent ryanodine receptor phosphorylation mediates sepsis‐induced cardiomyocyte apoptosis. J Cell Mol Med 2020; 24(17): 9627-37.
[] [PMID: 33460250]
Radeva MY, Waschke J. Mind the gap: mechanisms regulating the endothelial barrier. Acta Physiol 2018; 222(1): e12860.
[] [PMID: 28231640]
Jin J, Liu J, Luo Y, et al. High fructose induces dysfunctional vasodilatation via PP2A-mediated eNOS Ser1177 dephosphoryla-tion. Nutr Metab 2022; 19(1): 24.
[] [PMID: 35331293]
Ganbaatar B, Fukuda D, Shinohara M, et al. Inhibition of S1P receptor 2 attenuates endothelial dysfunction and inhibits ather-ogenesis in apolipoprotein E-deficient mice. J Atheroscler Thromb 2021; 28(6): 630-42.
[] [PMID: 32879149]
Ding J, Li Z, Li L, et al. Myosin light chain kinase inhibitor ML7 improves vascular endothelial dysfunction and permeability via the mitogen-activated protein kinase pathway in a rabbit model of atherosclerosis. Biomed Pharmacother 2020; 128: 110258.
[] [PMID: 32516749]
Kuzmich N, Sivak K, Chubarev V, Porozov Y, Savateeva-Lyubimova T, Peri F. TLR4 signaling pathway modulators as potential therapeutics in inflammation and sepsis. Vaccines 2017; 5(4): 34.
[] [PMID: 28976923]
Hui L, Yao Y, Wang S, et al. Inhibition of Janus kinase 2 and signal transduction and activator of transcription 3 protect against cecal ligation and puncture-induced multiple organ damage and mortality. J Trauma 2009; 66(3): 859-65.
[] [PMID: 19276765]
Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory dis-eases. Nat Rev Drug Discov 2018; 17(8): 588-606.
[] [PMID: 30026524]
Soroush F, Tang Y, Guglielmo K, et al. Protein Kinase C-Delta (PKCδ) tyrosine phosphorylation is a critical regulator of neu-trophil-endothelial cell interaction in inflammation. Shock 2019; 51(5): 538-47.
[] [PMID: 30095599]
Ince C, Mayeux PR, Nguyen T, et al. The endothelium in sepsis. Shock 2016; 45(3): 259-70.
[] [PMID: 26871664]
Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 1999; 24(5): 186-91.
[] [PMID: 10322434]
Mount PF, Kemp BE, Power DA. Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J Mol Cell Cardiol 2007; 42(2): 271-9.
[] [PMID: 16839566]
Dejana E, Orsenigo F, Lampugnani MG. The role of adherens junctions and VE-cadherin in the control of vascular permeabil-ity. J Cell Sci 2008; 121(13): 2115-22.
[] [PMID: 18565824]
Gavard J. Endothelial permeability and VE-cadherin. Cell Adhes Migr 2014; 8(2): 158-64.
[] [PMID: 25422846]
Vestweber D, Wessel F, Nottebaum AF. Similarities and differences in the regulation of leukocyte extravasation and vascular permeability. Semin Immunopathol 2014; 36(2): 177-92.
[] [PMID: 24638889]
Fox CJ, Hammerman PS, Thompson CB. Fuel feeds function: energy metabolism and the T-cell response. Nat Rev Immunol 2005; 5(11): 844-52.
[] [PMID: 16239903]
Harrois A, Huet O, Duranteau J. Alterations of mitochondrial function in sepsis and critical illness. Curr Opin Anaesthesiol 2009; 22(2): 143-9.
[] [PMID: 19390243]
Alves-Filho JC, Pålsson-McDermott EM. Pyruvate kinase M2: A potential target for regulating inflammation. Front Immunol 2016; 7: 145.
[] [PMID: 27148264]
Hüttemann M, Helling S, Sanderson TH, et al. Regulation of mitochondrial respiration and apoptosis through cell signaling: Cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation. Biochim Biophys Acta Bioenerg 2012; 1817(4): 598-609.
[] [PMID: 21771582]
Shenoy S. Coronavirus (Covid-19) sepsis: revisiting mitochondrial dysfunction in pathogenesis, aging, inflammation, and mortality. Inflamm Res 2020; 69(11): 1077-85.
[] [PMID: 32767095]
Sun Y, Shi H, Yin S, et al. Human mesenchymal stem cell derived exosomes alleviate type 2 diabetes mellitus by reversing pe-ripheral insulin resistance and relieving β-cell destruction. ACS Nano 2018; 12(8): 7613-28.
[] [PMID: 30052036]
Liu W, Yu M, Xie D, et al. Melatonin-stimulated MSC-derived exosomes improve diabetic wound healing through regulating macrophage M1 and M2 polarization by targeting the PTEN/AKT pathway. Stem Cell Res Ther 2020; 11(1): 259.
[] [PMID: 32600435]
Xu X, Yu H, Sun L, et al. Adipose derived mesenchymal stem cells ameliorate dibutyltin dichloride induced chronic pancreatitis by inhibiting the PI3K/AKT/mTOR signaling pathway. Mol Med Rep 2020; 21(4): 1833-40.
[] [PMID: 32319628]
Chen J, Chen J, Cheng Y, et al. Mesenchymal stem cell-derived exosomes protect beta cells against hypoxia-induced apop-tosis via miR-21 by alleviating ER stress and inhibiting p38 MAPK phosphorylation. Stem Cell Res Ther 2020; 11(1): 97.
[] [PMID: 32127037]
Na L, Wang S, Liu T, Zhang L. Ultrashort wave combined with Human Umbilical Cord Mesenchymal Stem Cell (HUC-MSC) transplantation inhibits nlrp3 inflammasome and improves spinal cord injury via MK2/TTP signalling pathway. BioMed Res Int 2020; 2020: 1-13.
[] [PMID: 33376718]
Zhou W, Silva M, Feng C, et al. Exosomes derived from human placental mesenchymal stem cells enhanced the recovery of spinal cord injury by activating endogenous neurogenesis. Stem Cell Res Ther 2021; 12(1): 174.
[] [PMID: 33712072]
Thomi G, Surbek D, Haesler V, Joerger-Messerli M, Schoeberlein A. Exosomes derived from umbilical cord mesenchymal stem cells reduce microglia-mediated neuroinflammation in perinatal brain injury. Stem Cell Res Ther 2019; 10(1): 105.
[] [PMID: 30898154]
Su VYF, Lin CS, Hung SC, Yang KY. Mesenchymal stem cell-conditioned medium induces neutrophil apoptosis associated with inhibition of the NF-κB pathway in endotoxin-induced acute lung injury. Int J Mol Sci 2019; 20(9): 2208.
[] [PMID: 31060326]
Wu KH, Wu HP, Chao WR, et al. Time-series expression of toll-like receptor 4 signaling in septic mice treated with mesenchy-mal stem cells. Shock 2016; 45(6): 634-40.
[] [PMID: 26682950]
Li D, Pan X, Zhao J, et al. Bone marrow mesenchymal stem cells suppress acute lung injury induced by lipopolysaccharide through inhibiting the TLR2, 4/NF-κB pathway in rats with multiple trauma. Shock 2016; 45(6): 641-6.
[] [PMID: 26717106]
Pedrazza L, Cubillos-Rojas M, de Mesquita FC, et al. Mesenchymal stem cells decrease lung inflammation during sepsis, act-ing through inhibition of the MAPK pathway. Stem Cell Res Ther 2017; 8(1): 289.
[] [PMID: 29273091]
Pan Q, Kuang X, Cai S, et al. miR-132-3p priming enhances the effects of mesenchymal stromal cell-derived exosomes on ameliorating brain ischemic injury. Stem Cell Res Ther 2020; 11(1): 260.
[] [PMID: 32600449]
Chen J, Li C, Liang Z, et al. Human mesenchymal stromal cells small extracellular vesicles attenuate sepsis-induced acute lung injury in a mouse model: the role of oxidative stress and the mitogen-activated protein kinase/nuclear factor kappa B pathway. Cytotherapy 2021; 23(10): 918-30.
[] [PMID: 34272174]
Mizuta Y, Akahoshi T, Guo J, et al. Exosomes from adipose tissue-derived mesenchymal stem cells ameliorate histone-induced acute lung injury by activating the PI3K/Akt pathway in endothelial cells. Stem Cell Res Ther 2020; 11(1): 508.
[] [PMID: 33246503]
Yu H, Lin L, Zhang Z, Zhang H, Hu H. Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther 2020; 5(1): 209.
[] [PMID: 32958760]
Coulthard LR, White DE, Jones DL, McDermott MF, Burchill SA. p38MAPK: stress responses from molecular mechanisms to therapeutics. Trends Mol Med 2009; 15(8): 369-79.
[] [PMID: 19665431]
Motegi S, Sekiguchi A, Uchiyama A, et al. Protective effect of mesenchymal stem cells on the pressure ulcer formation by the regulation of oxidative and endoplasmic reticulum stress. Sci Rep 2017; 7(1): 17186.
[] [PMID: 29215059]
Wang L, Qing L, Liu H, et al. Mesenchymal stromal cells ameliorate oxidative stress-induced islet endothelium apoptosis and functional impairment via Wnt4-β-catenin signaling. Stem Cell Res Ther 2017; 8(1): 188.
[] [PMID: 28807051]
Xu Z, Huang Y, Mao P, Zhang J, Li Y. Sepsis and ARDS: The dark side of histones. Mediators Inflamm 2015; 2015: 1-9.
[] [PMID: 26609197]

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