Peripheral infusion of human umbilical cord mesenchymal stem cells rescues acute liver failure lethality in monkeys
Tóm tắt
Acute liver failure (ALF) is a complicated clinical syndrome associated with high mortality, with liver transplantation as the only treatment option. Treatment of mesenchymal stem cells has shown a potential therapeutic option for acute liver failure. However, the lack of random clinical trials and large non-human primate studies makes it necessary to assess the efficacy and safety in the clinic. We treated the monkeys with peripheral delivery of human umbilical MSCs (hUC-MSCs) and investigated the role of hUC-MSCs in modulating the progress of acute liver failure. The use of early peripheral infusion of human umbilical cord MSC infusion did not improve liver regeneration or modulate adaptive immunity. However, it significantly suppressed the hepatic aggregation and maturation of circulating monocytes and their IL-6 secretion, greatly improving liver histology, systemic homeostasis, and survival. Our study reveals the critical role of monocyte-derived IL-6 in initiating and accelerating acute liver failure and hUC-MSC treatment can disrupt the development of the inflammatory cascade by inhibiting monocyte activation. Early hUC-MSC treatment disrupts the development of the inflammatory cascade, indicating a potential clinical solution for acute liver failure.
Tài liệu tham khảo
Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2013;369:2525–34.
Sarin SK, Choudhury A. Acute-on-chronic liver failure: terminology, mechanisms and management. Nat Rev Gastroenterol Hepatol. 2016;13:131–49.
Arroyo V, Jalan R. Acute-on-chronic liver failure: definition, diagnosis, and clinical characteristics. Semin Liver Dis. 2016;36:109–16.
O'Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet (London, England). 1993;342:273–5.
Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatol (Baltimore, Md). 2000;32:734–9.
Sarin SK, Choudhury A. Management of acute-on-chronic liver failure: an algorithmic approach. Hepatol Int. 2018;12:402. https://doi.org/10.1007/s12072-018-9887-5.
Antoniades CG, Quaglia A, Taams LS, Mitry RR, Hussain M, Abeles R, et al. Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans. Hepatol (Baltimore, Md). 2012;56:735–46.
Possamai LA, Thursz MR, Wendon JA, Antoniades CG. Modulation of monocyte/macrophage function: a therapeutic strategy in the treatment of acute liver failure. J Hepatol. 2014;61:439–45.
Guo G, Zhu Y, Wu Z, Ji H, Lu X, Zhou Y, et al. Circulating monocytes accelerate acute liver failure by IL-6 secretion in monkey. 2018.
Zhou P, Xia J, Guo G, Huang ZX, Lu Q, Li L, et al. A Macaca mulatta model of fulminant hepatic failure. World J Gastroenterol. 2012;18:435–44.
Ren G, Chen X, Dong F, Li W, Ren X, Zhang Y, et al. Concise review: mesenchymal stem cells and translational medicine: emerging issues. Stem Cells Transl Med. 2012;1:51–8.
Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17:11–22.
Squillaro T, Peluso G, Galderisi U. Clinical trials with mesenchymal stem cells: an update. Cell Transplant. 2016;25:829–48.
Herrera MB, Fonsato V, Bruno S, Grange C, Gilbo N, Romagnoli R, et al. Human liver stem cells improve liver injury in a model of fulminant liver failure. Hepatol (Baltimore, Md). 2013;57:311–9.
Yi T, Song SU. Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications. Arch Pharm Res. 2012;35:213–21.
Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med. 2012;1:725–31.
Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13:392–402.
Volarevic V, Nurkovic J, Arsenijevic N, Stojkovic M. Concise review: therapeutic potential of mesenchymal stem cells for the treatment of acute liver failure and cirrhosis. Stem Cells (Dayton, Ohio). 2014;32:2818–23.
Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ, et al. Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem cells (Dayton, Ohio). 2004;22:1330–7.
Ding DC, Chang YH, Shyu WC, Lin SZ. Human umbilical cord mesenchymal stem cells: a new era for stem cell therapy. Cell Transplant. 2015;24:339–47.
Gao F, Chiu SM, Motan DA, Zhang Z, Chen L, Ji HL, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 2016;7:e2062.
Amable PR, Teixeira MV, Carias RB, Granjeiro JM, Borojevic R. Protein synthesis and secretion in human mesenchymal cells derived from bone marrow, adipose tissue and Wharton’s jelly. Stem Cell Res Ther. 2014;5:53.
Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci U S A. 2007;104:7217–22.
Mengs U, Pohl RT, Mitchell T. Legalon(R) SIL: the antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning. Curr Pharm Biotechnol. 2012;13:1964–70.
Trabulus S, Altiparmak MR. Clinical features and outcome of patients with amatoxin-containing mushroom poisoning. Clin Toxicol (Philadelphia, Pa). 2011;49:303–10.
Fiume L. Mechanism of action of amanitins. Curr Probl Clin Biochem. 1977;7:23–8.
Leithead JA, Ferguson JW, Bates CM, Davidson JS, Lee A, Bathgate AJ, et al. The systemic inflammatory response syndrome is predictive of renal dysfunction in patients with non-paracetamol-induced acute liver failure. Gut. 2009;58:443–9.
Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448–57.
Moller HJ, Gronbaek H, Schiodt FV, Holland-Fischer P, Schilsky M, Munoz S, et al. Soluble CD163 from activated macrophages predicts mortality in acute liver failure. J Hepatol. 2007;47:671–6.
Serbina NV, Pamer EG. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol. 2006;7:311–7.
McGuinness PH, Painter D, Davies S, McCaughan GW. Increases in intrahepatic CD68 positive cells, MAC387 positive cells, and proinflammatory cytokines (particularly interleukin 18) in chronic hepatitis C infection. Gut. 2000;46:260–9.
Wensink AC, Kemp V, Fermie J, Garcia Laorden MI, van der Poll T, Hack CE, et al. Granzyme K synergistically potentiates LPS-induced cytokine responses in human monocytes. Proc Natl Acad Sci U S A. 2014;111:5974–9.
Antoniades CG, Berry PA, Wendon JA, Vergani D. The importance of immune dysfunction in determining outcome in acute liver failure. J Hepatol. 2008;49:845–61.
Yang Q, Shi Y, He J, Chen Z. The evolving story of macrophages in acute liver failure. Immunol Lett. 2012;147:1–9.
Streetz KL, Luedde T, Manns MP, Trautwein C. Interleukin 6 and liver regeneration. Gut. 2000;47:309–12.
Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, Kishimoto T, et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature. 1994;368:339–42.
Heslop JA, Hammond TG, Santeramo I, Tort Piella A, Hopp I, Zhou J, et al. Concise review: workshop review: understanding and assessing the risks of stem cell-based therapies. Stem Cells Transl Med. 2015;4:389–400.