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Cited by 25Liver physiology and pathologyInflammasome and immune disordersMesenchymal stem cell research

Stem Cells From Human Exfoliated Deciduous Teeth Alleviate Liver Cirrhosis via Inhibition of Gasdermin D-Executed Hepatocyte Pyroptosis

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Chen, Peng, Zhou, Yi-kun, Han, Chun-shan, Chen, Liu-jing, Wang, Yi-ming, Zhuang, Zi-meng, Lin, Shuai, Zhou, Yan-heng +2 more·2022·Frontiers in Immunology
DOI 10.3389/fimmu.2022.860225PMC PMC9133376
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Abstract

Liver cirrhosis represents a type of end-stage liver disease with few effective therapies, which was characterized by damaged functional liver tissue due to long-term inflammation. Gasdermin D (GSDMD)-executed programmed necrosis is reported to be involved in inflammation. However, the role of GSDMD in liver cirrhosis remains unclear. In this study, we used a CCl 4-induced cirrhosis model and found stem cells from human exfoliated deciduous teeth (SHED) infusion showed profound therapeutic effects for liver cirrhosis. Mechanistically, NLRP3 inflammasome-activated GSDMD and its pyroptosis were upregulated in liver cirrhosis, while SHED infusion could suppress the expression of GSDMD and Caspase-1, resulting in reduced hepatocyte pyroptosis and inflammatory cytokine IL-1β release. Consistently, SHED could inhibit the elevated expression of NLRP3, GSDMD and Caspase-1 induced by CCl 4 treatment in vitro co-culture system, which was mediated by decreasing reactive oxygen species (ROS) generation. Moreover, the pyroptosis inhibitor disulfiram showed similar therapeutic effects for liver cirrhosis as SHED. In conclusion, SHED alleviates CCl 4-induced liver cirrhosis via inhibition of hepatocytes pyroptosis. Our findings could provide a potential treatment strategy and novel target for liver cirrhosis.

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  1. [1]Sepanlou SG Safiri S Bisignano C Ikuta KS Merat S Saberifiroozi M. The Global, Regional, and National Burden of Cirrhosis by Cause in 195 Countries and Territories, 1990–2017: A Systematic Analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol (2020) 5: 245–66. doi: 10.1016/S2468-1253(19)30349-8 PMC7026710 31981519 · DOI · Paper page
  2. [2]Pellicoro A Ramachandran P Iredale JP Fallowfield JA. Liver Fibrosis and Repair: Immune Regulation of Wound Healing in a Solid Organ. Nat Rev Immunol (2014) 14: 181–94. doi: 10.1038/nri3623 24566915 · DOI · Paper page
  3. [3]Murray KF Carithers RL. AASLD Practice Guidelines: Evaluation of the Patient for Liver Transplantation. Hepatology (2005) 41: 1407–32. doi: 10.1002/hep.20704 15880505 · DOI
  4. [4]Petersen BE Bowen WC Patrene KD Mars WM Sullivan AK Murase N. Bone Marrow as a Potential Source of Hepatic Oval Cells. Science (1999) 284: 1168–70. doi: 10.1126/science.284.5417.1168 10325227 · DOI
  5. [5]Fang S-B Zhang H-Y Wang C He B-X Liu X-Q Meng X-C. Small Extracellular Vesicles Derived From Human Mesenchymal Stromal Cells Prevent Group 2 Innate Lymphoid Cell-Dominant Allergic Airway Inflammation Through Delivery of miR-146a-5p. J Extracell Vesicles (2020) 9: 1723260. doi: 10.1080/20013078.2020.1723260 32128074 PMC7034457 · DOI
  6. [6]Petrou P Kassis I Levin N Paul F Backner Y Benoliel T. Beneficial Effects of Autologous Mesenchymal Stem Cell Transplantation in Active Progressive Multiple Sclerosis. Brain (2020) 143: 3574–88. doi: 10.1093/brain/awaa333 33253391 · DOI
  7. [7]Zhu R Yan T Feng Y Liu Y Cao H Peng G. Mesenchymal Stem Cell Treatment Improves Outcome of COVID-19 Patients via Multiple Immunomodulatory Mechanisms. Cell Res (2021) 31: 1244–62. doi: 10.1038/s41422-021-00573-y PMC8546390 34702946 · DOI
  8. [8]Friedenstein AJ Deriglasova UF Kulagina NN Panasuk AF Rudakowa SF Luriá EA. Precursors for Fibroblasts in Different Populations of Hematopoietic Cells as Detected by the In Vitro Colony Assay Method. Exp Hematol (1974) 2: 83– 92. 4455512
  9. [9]Katz AJ Tholpady A Tholpady SS Shang H Ogle RC. Cell Surface and Transcriptional Characterization of Human Adipose-Derived Adherent Stromal (hADAS) Cells. Stem Cells (2005) 23: 412–23. doi: 10.1634/stemcells.2004-0021 15749936 · DOI
  10. [10]Seo B-M Miura M Gronthos S Bartold PM Batouli S Brahim J. Investigation of Multipotent Postnatal Stem Cells From Human Periodontal Ligament. Lancet (2004) 364: 149–55. doi: 10.1016/S0140-6736(04)16627-0 15246727 · DOI
  11. [11]Gronthos S Mankani M Brahim J Robey PG Shi S. Postnatal Human Dental Pulp Stem Cells (DPSCs) In Vitro and In Vivo. Proc Natl Acad Sci USA (2000) 97: 13625–30. doi: 10.1073/pnas.240309797 PMC17626 11087820 · DOI
  12. [12]Xie J Zhao YM Rao NQ Wang XT Fang TJ Li XX. Comparative Study of Differentiation Potential of Mesenchymal Stem Cells Derived From Orofacial System Into Vascular Endothelial Cells. Beijing Da Xue Xue Bao Yi Xue Ban (2019) 51: 900–6. doi: 10.19723/j.issn.1671-167X.2019.05.018 PMC7433536 31624396 · DOI
  13. [13]Yamaguchi S Shibata R Yamamoto N Nishikawa M Hibi H Tanigawa T. Dental Pulp-Derived Stem Cell Conditioned Medium Reduces Cardiac Injury Following Ischemia-Reperfusion. Sci Rep (2015) 5: 16295. doi: 10.1038/srep16295 26542315 PMC4635346 · DOI
  14. [14]Yamaza T Alatas FS Yuniartha R Yamaza H Fujiyoshi JK Yanagi Y. In Vivo Hepatogenic Capacity and Therapeutic Potential of Stem Cells From Human Exfoliated Deciduous Teeth in Liver Fibrosis in Mice. Stem Cell Res Ther (2015) 6: 171. doi: 10.1186/s13287-015-0154-6 26358689 PMC4566368 · DOI
  15. [15]Yokoyama T Yagi Mendoza H Tanaka T Ii H Takano R Yaegaki K. Regulation of CCl4-Induced Liver Cirrhosis by Hepatically Differentiated Human Dental Pulp Stem Cells. Hum Cell (2019) 32: 125–40. doi: 10.1007/s13577-018-00234-0 30637566 · DOI
  16. [16]Zhou Y-K Zhu L-S Huang H-M Cui S-J Zhang T Zhou Y-H. Stem Cells From Human Exfoliated Deciduous Teeth Ameliorate Concanavalin A-Induced Autoimmune Hepatitis by Protecting Hepatocytes From Apoptosis. World J Stem Cells (2020) 12: 1623–39. doi: 10.4252/wjsc.v12.i12.1623 PMC7789126 33505604 · DOI
  17. [17]Wang D Zheng J Hu Q Zhao C Chen Q Shi P. Magnesium Protects Against Sepsis by Blocking Gasdermin D N-Terminal-Induced Pyroptosis. Cell Death Differ (2020) 27: 466–81. doi: 10.1038/s41418-019-0366-x PMC7206066 31209359 · DOI
  18. [18]Beckwith KS Beckwith MS Ullmann S Sætra RS Kim H Marstad A. Plasma Membrane Damage Causes NLRP3 Activation and Pyroptosis During Mycobacterium Tuberculosis Infection. Nat Commun (2020) 11: 2270. doi: 10.1038/s41467-020-16143-6 32385301 PMC7210277 · DOI · Paper page
  19. [19]Doitsh G Galloway NL Geng X Yang Z Monroe KM Zepeda O. Cell Death by Pyroptosis Drives CD4 T-Cell Depletion in HIV-1 Infection. Nature (2014) 505: 509–14. doi: 10.1038/nature12940 PMC4047036 24356306 · DOI
  20. [20]Li S Wu Y Yang D Wu C Ma C Liu X. Gasdermin D in Peripheral Myeloid Cells Drives Neuroinflammation in Experimental Autoimmune Encephalomyelitis. J Exp Med (2019) 216: 2562–81. doi: 10.1084/jem.20190377 PMC6829591 31467036 · DOI
  21. [21]Koh EH Yoon JE Ko MS Leem J Yun J-Y Hong CH. Sphingomyelin Synthase 1 Mediates Hepatocyte Pyroptosis to Trigger Non-Alcoholic Steatohepatitis. Gut (2021) 70: 1954–64. doi: 10.1136/gutjnl-2020-322509 PMC8458090 33208407 · DOI
  22. [22]Sakaida I Terai S Yamamoto N Aoyama K Ishikawa T Nishina H. Transplantation of Bone Marrow Cells Reduces CCl4-Induced Liver Fibrosis in Mice. Hepatology (2004) 40: 1304–11. doi: 10.1002/hep.20452 15565662 · DOI
  23. [23]Hayasaka A Koch J Schuppan D Maddrey WC Hahn EG. The Serum Concentrations of the Aminoterminal Propeptide of Procollagen Type-III and the Hepatic Content of Messenger-Rna for the Alpha-1 Chain of Procollagen Type-Iii in Carbon Tetrachloride-Induced Rat-Liver Fibrogenesis. J Hepatol (1991) 13: 328–38. doi: 10.1016/0168-8278(91)90077-O 1725528 · DOI
  24. [24]Bergsbaken T Fink SL Cookson BT. Pyroptosis: Host Cell Death and Inflammation. Nat Rev Microbiol (2009) 7: 99– 109. doi: 10.1038/nrmicro2070 19148178 PMC2910423 · DOI
  25. [25]Hirsova P Gores GJ. Death Receptor-Mediated Cell Death and Proinflammatory Signaling in Nonalcoholic Steatohepatitis. Cell Mol Gastroenterol Hepatol (2015) 1: 17– 27. doi: 10.1016/j.jcmgh.2014.11.005 25729762 PMC4340657 · DOI
  26. [26]Xu B Jiang M Chu Y Wang W Chen Di Li X. Gasdermin D Plays a Key Role as a Pyroptosis Executor of Non-Alcoholic Steatohepatitis in Humans and Mice. J Hepatol (2018) 68: 773–82. doi: 10.1016/j.jhep.2017.11.040 29273476 · DOI · Paper page
  27. [27]Kayagaki N Warming S Lamkanfi M Vande Walle L Louie S Dong J. Non-Canonical Inflammasome Activation Targets Caspase-11. Nature (2011) 479: 117–21. doi: 10.1038/nature10558 22002608 · DOI · Paper page
  28. [28]Xia S Zhang Z Magupalli VG Pablo JL Dong Y Vora SM. Gasdermin D Pore Structure Reveals Preferential Release of Mature Interleukin-1. Nature (2021) 593: 607–11. doi: 10.1038/s41586-021-03478-3 PMC8588876 33883744 · DOI
  29. [29]Man SM Ekpenyong A Tourlomousis P Achouri S Cammarota E Hughes K. Actin Polymerization as a Key Innate Immune Effector Mechanism to Control Salmonella Infection. Proc Natl Acad Sci USA (2014) 111: 17588–93. doi: 10.1073/pnas.1419925111 PMC4267384 25422455 · DOI
  30. [30]Hu JJ Liu X Xia S Zhang Z Zhang Y Zhao J. FDA-Approved Disulfiram Inhibits Pyroptosis by Blocking Gasdermin D Pore Formation. Nat Immunol (2020) 21: 736–45. doi: 10.1038/s41590-020-0669-6 PMC7316630 32367036 · DOI · Paper page
  31. [31]Amir M Czaja MJ. Inflammasome-Mediated Inflammation and Fibrosis: It Is More Than Just the IL-1β. Hepatology (2018) 67: 479–81. doi: 10.1002/hep.29491 PMC5832548 28862748 · DOI
  32. [32]Strowig T Henao-Mejia J Elinav E Flavell R. Inflammasomes in Health and Disease. Nature (2012) 481: 278–86. doi: 10.1038/nature10759 22258606 · DOI · Paper page
  33. [33]Shi J Zhao Y Wang K Shi X Wang Y Huang H. Cleavage of GSDMD by Inflammatory Caspases Determines Pyroptotic Cell Death. Nature (2015) 526: 660–5. doi: 10.1038/nature15514 26375003 · DOI · Paper page
  34. [34]Wang K Sun Q Zhong X Zeng M Zeng H Shi X. Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis. Cell (2020) 180: 941–55.e20. doi: 10.1016/j.cell.2020.02.002 32109412 · DOI
  35. [35]Khanova E Wu R Wang W Yan R Chen Y French SW. Pyroptosis by Caspase11/4-Gasdermin-D Pathway in Alcoholic Hepatitis in Mice and Patients. Hepatology (2018) 67: 1737–53. doi: 10.1002/hep.29645 PMC5906140 29108122 · DOI · Paper page
  36. [36]Saeki N Sasaki H. Gasdermin Superfamily: A Novel Gene Family Functioning in Epithelial Cells. J Carrasco M Mota, editors. Endothelium and Epithelium (2012) pp. 193– 211.
  37. [37]Das S Miller M Beppu AK Mueller J McGeough MD Vuong C. GSDMB Induces an Asthma Phenotype Characterized by Increased Airway Responsiveness and Remodeling Without Lung Inflammation. Proc Natl Acad Sci USA (2016) 113: 13132–7. doi: 10.1073/pnas.1610433113 PMC5135378 27799535 · DOI
  38. [38]Li Y Yuan Y Huang Z Chen H Lan R Wang Z. GSDME-Mediated Pyroptosis Promotes Inflammation and Fibrosis in Obstructive Nephropathy. Cell Death Differ (2021) 28: 2333–50. doi: 10.1038/s41418-021-00755-6 PMC8329275 33664482 · DOI
  39. [39]Kovacs SB Miao EA. Gasdermins: Effectors of Pyroptosis. Trends Cell Biol (2017) 27: 673–84. doi: 10.1016/j.tcb.2017.05.005 PMC5565696 28619472 · DOI
  40. [41]Xi R Montague J Lin X Lu C Lei W Tanaka K. Up-Regulation of Gasdermin C in Mouse Small Intestine Is Associated With Lytic Cell Death in Enterocytes in Worm-Induced Type 2 Immunity. Proc Natl Acad Sci USA (2021) 118: e2026307118. doi: 10.1073/pnas.2026307118 34290141 PMC8325246 · DOI
  41. [42]Fuller RK Branchey L Brightwell DR Derman RM Emrick CD Iber FL. Disulfiram Treatment of Alcoholism. A Veterans Administration Cooperative Study. JAMA (1986) 256: 1449–55. doi: 10.1001/jama.256.11.1449 3528541 · DOI
  42. [44]Kroemer G Galluzzi L Brenner C. Mitochondrial Membrane Permeabilization in Cell Death. Physiol Rev (2007) 87: 99– 163. doi: 10.1152/physrev.00013.2006 17237344 · DOI · Paper page
  43. [45]Evavold CL Hafner-Bratkovič I Devant P D'Andrea JM Ngwa EM Boršić E. Control of Gasdermin D Oligomerization and Pyroptosis by the Ragulator-Rag-Mtorc1 Pathway. Cell (2021) 184: 4495– 511.e19. doi: 10.1016/j.cell.2021.06.028 34289345 PMC8380731 · DOI
  44. [46]Li Y Shen Y Jin K Wen Z Cao W Wu B. The DNA Repair Nuclease MRE11A Functions as a Mitochondrial Protector and Prevents T Cell Pyroptosis and Tissue Inflammation. Cell Metab (2019) 30: 477– 92.e6. doi: 10.1016/j.cmet.2019.06.016 31327667 PMC7093039 · DOI
  45. [47]Zhou R Yazdi AS Menu P Tschopp J. A Role for Mitochondria in NLRP3 Inflammasome Activation. Nature (2011) 469: 221–5. doi: 10.1038/nature09663 21124315 · DOI · Paper page
  46. [48]Choi JS Jeong IS Han JH Cheon SH Kim S-W. IL-10-Secreting Human MSCs Generated by TALEN Gene Editing Ameliorate Liver Fibrosis Through Enhanced Anti-Fibrotic Activity. Biomater Sci (2019) 7: 1078–87. doi: 10.1039/c8bm01347k 30631870 · DOI
  47. [49]Parekkadan B van Poll D Megeed Z Kobayashi N Tilles AW Berthiaume F. Immunomodulation of Activated Hepatic Stellate Cells by Mesenchymal Stem Cells. Biochem Biophys Res Commun (2007) 363: 247–52. doi: 10.1016/j.bbrc.2007.05.150 PMC2096777 17869217 · DOI
  48. [50]Yang Y Chen Q-H Liu A-R Xu X-P Han J-B Qiu H-B. Synergism of MSC-Secreted HGF and VEGF in Stabilising Endothelial Barrier Function Upon Lipopolysaccharide Stimulation via the Rac1 Pathway. Stem Cell Res Ther (2015) 6: 250. doi: 10.1186/s13287-015-0257-0 26674641 PMC4682264 · DOI
  49. [51]Hough KP Trevor JL Strenkowski JG Wang Y Chacko BK Tousif S. Exosomal Transfer of Mitochondria From Airway Myeloid-Derived Regulatory Cells to T Cells. Redox Biol (2018) 18: 54– 64. doi: 10.1016/j.redox.2018.06.009 29986209 PMC6031096 · DOI
  50. [52]Cai G Cai G Zhou H Zhuang Z Liu K Pei S. Mesenchymal Stem Cell-Derived Exosome miR-542-3p Suppresses Inflammation and Prevents Cerebral Infarction. Stem Cell Res Ther (2021) 12: 2. doi: 10.1186/s13287-020-02030-w 33407827 PMC7786953 · DOI
  51. [53]Li X Michaeloudes C Zhang Y Wiegman CH Adcock IM Lian Q. Mesenchymal Stem Cells Alleviate Oxidative Stress-Induced Mitochondrial Dysfunction in the Airways. J Allergy Clin Immunol (2018) 141: 1634– 45.e5. doi: 10.1016/j.jaci.2017.08.017 28911970 · DOI
  52. [54]Akiyama K Chen C Wang D Xu X Qu C Yamaza T. Mesenchymal-Stem-Cell-Induced Immunoregulation Involves FAS-Ligand-/FAS-Mediated T Cell Apoptosis. Cell Stem Cell (2012) 10: 544–55. doi: 10.1016/j.stem.2012.03.007 PMC3348385 22542159 · DOI
  53. [55]Galleu A Riffo-Vasquez Y Trento C Lomas C Dolcetti L Cheung TS. Apoptosis in Mesenchymal Stromal Cells Induces In Vivo Recipient-Mediated Immunomodulation. Sci Transl Med (2017) 9: eaam7828. doi: 10.1126/scitranslmed.aam7828 29141887 · DOI
  54. [56]Wang HY Li C Liu WH Deng FM Ma Y Guo LN. Autophagy Inhibition via Becn1 Downregulation Improves the Mesenchymal Stem Cells Antifibrotic Potential in Experimental Liver Fibrosis. J Cell Physiol (2020) 235: 2722–37. doi: 10.1002/jcp.29176 PMC6916329 31508820 · DOI

Cited by

Sorted by citations

Authors
Chen, P., Zhou, Y.-K., Han, C.-S., Chen, L.-J., Wang, Y.-M., Zhuang, Z.-M., Lin, S., Zhou, Y.-H., Jiang, J.-H., & Yang, R.-L.
Affiliations
Peking University (CN)
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2022-05-12
Volume
13
Pages
860225-860225
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2022.860225
PMC
PMC9133376
OpenAlex
W4280539438
Cited by
25
References
2
Citations by year
2026: 2 · 2025: 10 · 2024: 9 · 2023: 4
FWCI
3.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Natural Science Foundation of China (81970940)
  • Recruitment Program of Global Experts
  • National Science and Technology Major Project (2018ZX10302207)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
liver cirrhosis, stem cells from human exfoliated deciduous teeth, sheds, hepatocyte pyroptosis, gasdermin D, NLRP3 inflammasome, caspase-1, IL-1β, reactive oxygen species, carbon tetrachloride-induced liver injury, disulfiram, cell therapy
MeSH terms
Pyroptosis, NLR Family, Pyrin Domain-Containing 3 Protein, Humans, Inflammation, Liver Cirrhosis, Stem Cells, Tooth, Deciduous, Caspase 1, Hepatocytes, Phosphate-Binding Proteins, Intracellular Signaling Peptides and Proteins

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