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Khirurgii

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Year 2017 Vol. 25 No 2

REVIEWS

A.T. SHCHASTNY, S.A. SUSHKOU, O.D. MYADELETS, E.I. LEBEDEVA

CHALLENGES AND PROSPECTS OF CELLULAR THERAPY IN TREATMENT OF LIVER DISEASES

EE "Vitebsk State Medical University",
Vitebsk
The Republic of Belarus

It is reported on the results of an international experience, reflecting the achievements in the field of studying of the possibilities of stem cell use in the treatment of pathological processes in the liver, as well as the challenges and prospects of development of this field in medicine. Clinical application of the stem cells for the treatment of liver disease is on the initial stage. Many problems requiring careful investigation are still occurred. One of the main objectives is a search of the optimal source of cells. The priority is given to the optimization of cryo-storage techniques. An actual problem remains the poor survival rate of the cells and elimination by the immune system within a few months after transplantation. There is no consensus on the number of transplanted cells, the multiplicity of ways of their administration, adjuvant therapy with cytokines and growth factors for receiving optimal results. The mechanism of differentiation in hepatocyte direction remains insufficiently studied and controversial. There is a security problem, in particular, related to the possible development of fibrosis involved the transplanted cells, which can aggrevate the course of disease. Despite the absence of direct evidence, there is wariness about the risks of oncogenic transformation of mesenchymal stem cells, as all stem cells have the capacity to self-renew by dividing similar to that of the tumor cells. No optimal method of visualization of transplanted cells exists yet. These problems requires the further laborious research in vitro and in vivo. Overview of the properties of these different types of stem cells can serve as a starting point for researchers working in the conditions of rapid development of stem cell engineering and cell therapy.

Keywords: liver regeneration, differentiation, transplantation, stem cells of the liver and extrahepatic origin cells, stem cell engineering, cell therapy
p. 183-193 of the original issue
References
  1. Ezquer F, Bruna F, Calligaris S, Conget P, Ezquer M. Multipotent mesenchymal stromal cells: A promising strategy to manage alcoholic liver disease. World J Gastroenterol. 2016 Jan;22(1):24-36. doi: 10.3748/wjg.v22.i1.24.
  2. Collin de l’Hortet A, Takeishi K, Guzman-Lepe J, Handa K, Matsubara K, Fukumitsu K, et al. Liver-regenerative transplantation: regrow and reset. Am J Transplant. 2016 Jun;16(6):1688-96. doi: 10.1111/ajt.13678.
  3. Zhou Q, Li L, Li J. Stem cells with decellularized liver scaffolds in liver regeneration and their potential clinical applications. Liver Int. 2015 Mar;35(3):687-94. doi: 10.1111/liv.12581.
  4. Tsolaki E, Yannaki E. Stem cell-based regenerative opportunities for the liver: State of the art and beyond. World J Gastroenterol. 2015 Nov;21(43):12334-50. doi: 10.3748/wjg.v21.i43.12334.
  5. Wang B, Zhao L, Fish M, Logan CY, Nusse R. Self-renewing diploid axin2+ cells fuel homeostatic renewal of the liver. Nature. 2015 Aug;524(7564):180-85. doi: 10.1038/nature14863.
  6. Uryvaeva IV. Stvolovye kletki v regeneratsii pecheni [Stem cells in liver regeneration]. V kn: Pal'tsev MA, red. Biologiia stvolovykh kletok i kletochnye tekhnologii. Moscow, RF; 2009;2. p. 211-253.
  7. Navarro-Alvarez N, Soto-Gutierrez A, Kobayashi N. Hepatic stem cells and liver development. Methods Mol Biol. 2010;640:181-36. doi: 10.1007/978-1-60761-688-7_10.
  8. Chen YH, Chen HL, Chien CS, Wu SH, Ho YT, Yu CH, et al. Contribution of mature hepatocytes to biliary regeneration in rats with acute and chronic biliary injury. Plos One. 2015 Aug;10(8):e0134327. doi: 10.1371/journal.pone.0134327. eCollection 2015.
  9. Petrakova OS, Chernioglo ES, Terskikh VV, Kalistratova AV. Ispol'zovanie kletochnykh tekhnologii v lechenii patologii pecheni [The use of cellular technology in the treatment of liver pathologies]. Acta Naturae. 2012;4(3):18-33.
  10. Tanimizu N, Mitaka T. Re-evaluation of liver stem/progenitor cells. Organogenesis. 2014 Apr-Jun;10(2):208-15. doi: 10.4161/org.27591.
  11. Hu C, Li L. In vitro culture of isolated primary hepatocytes and stem cell-derived hepatocyte-like cells for liver regeneration. Protein Cell. 2015 Aug;6(8):562-74. doi: 10.1007/s13238-015-0180-2.
  12. Zhang W, Chen XP, Zhang WG, Zhang F, Xiang S, Dong HH, et al. Hepatic non-parenchymal cells and extracellular matrix participate in oval cell-mediated liver regeneration. World J Gastroenterol. 2009 Feb;15(5):552-60. doi: 10.3748/wjg.15.552.
  13. Martinez-Palacian A, del Castillo G, Suarez-Causado A, Garcia-Alvaro M, de Morena-Frutos D, Fernandez M, et al. Mouse hepatic oval cells require met-dependent PI3K to impair TGF-b-induced oxidative stress and apoptosis. Plos One. 2013 Jan;8(1):e53108. doi: 10.1371/journal.pone.0053108.
  14. Liedtke C, Luedde T, Sauerbruch T, Scholten D, Streetz K, Tacke F, et al. Experimental liver fibrosis research: update on animal models, legal issues and translational aspects. Fibrogenesis Tissue Repair. 2013 Oct;6(1):19. doi: 10.1186/1755-1536-6-19.
  15. Dolgikh MS. Perspektivy terapii pechenochnoi nedostatochnosti s pomoshch'iu stvolovykh kletok [Prospects for therapy of liver failure with stem cells]. Biomed Khimiia. 2008;54(4):376-91.
  16. Huch M, Dorrell C, Boj SF, van Es JH, Li VS, van de Wetering M, et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature. 2013 Feb;494(7436):247-50. doi: 10.1038/nature11826.
  17. Mitaka T; Ooe H. Characterization of hepatic-organoid cultures. Drug Metab Rev. 2010 Aug;42(3):472-81. doi: 10.3109/03602530903492020.
  18. Yoshizato K. Growth potential of adult hepatocytes in mammals: highly replicative small hepatocytes with liver progenitor-like traits. Dev Growth Differ. 2007 Feb;49(2):171-84. doi: 10.1111/j.1440-169x.2007.00918.x.
  19. Szkolnicka D, Hay DC. Concise review: advances in generating hepatocytes from pluripotent stem cells for translational medicine. Stem Cells. 2016 Jun;34(6):1421-26. doi: 10.1002/stem.2368.
  20. Labeznik LB, Golovanova EV, Slupskaia VA, Trubitsyna IE, Gendrikson LN, Kniazev OV, i dr. Realii i perspektivy ispol'zovaniia kletochnykh tekhnologii dlia lecheniia khronicheskikh diffuznykh zabolevanii pecheni [Realities and prospects for the use of cell technologies for the treatment of chronic diffuse liver diseases]. Eksperim i Klin Gastroenterologiia. 2011;(6):3-10.
  21. Katoonizadeh A, Poustchi H, Malekzadeh R. Hepatic progenitor cells in liver regeneration: current advances and clinical perspectives. Liver Int. 2014 Nov;34(10):1464-72. doi: 10.1111/liv.12573.
  22. Hamooda M. Hepatocyte transplantation in children with liver cell failure. Electron Physician. 2016 Oct;8(10):3096-01. doi: 10.19082/3096.
  23. Aleksandrov VN, Kamilova TA, Kaliuzhnaia LI, Kriventsov AV, Firsanov DV, Chirskii VS, i dr. Kletochnaia terapiia tsirroza pecheni [Cell therapy of liver cirrhosis]. Vestn Ros Voen-Med Akad. 2014;(1):197-202.
  24. Wang Y, Yu X, Chen E, Li L. Liver-derived human mesenchymal stem cells: a novel therapeutic source for liver diseases. Stem Cell Res Ther. 2016 May;7(1):71. doi: 10.1186/s13287-016-0330-3.
  25. Adas G, Koc B, Adas M, Duruksu G, Subasi C, Kemik O, et al. Effects of mesenchymal stem cells and VEGF on liver regeneration following major resection. Langenbecks Arch Surg. 2016 Aug;401(5):725-40. doi: 10.1007/s00423-016-1380-9.
  26. Shevela EY, Starostina NM, Pal’tsev AI, Shipunov MV, Zheltova OI, Meledina IV, et al. Efficiency of cell therapy in liver cirrhosis. Bull Exp in Biol Med. 2016 Feb;160(4):542-47. doi: 10.1007/s10517-016-3215-7.
  27. Oldhafer F, Bock M, Falk CS, Vondran FWR. Immunological aspects of liver cell transplantation. World J Transplant. 2016 Mar;6(1):42-53. doi: 10.5500/wjt.v6.i1.42.
  28. Labeznik LB, Golovanova EV, Slupskaia VA, Kniazev OV, Gedrikson LN, Khomeriki SG, i dr. Mezenkhimal'nye stvolovye kletki v lechenii khronicheskikh zabolevanii pecheni – ot eksperimenta k klinicheskoi praktike [Mesenchymal stem cells in the treatment of chronic liver diseases - from the experiment to clinical practice]. Eksperim i Klin Gastroenterologiia. 2012;(6):13-19.
  29. Sayyed HG, Osama A, Idriss NK, Sabry D, Abdelrhim AS, Bakry R. Comparison of the therapeutic effectiveness of human CD34+ and rat bone marrow mesenchymal stem cells on improvement of experimental liver firosis in Wistar rats. Int J Physiol Pathophysiol Pharmacol. 2016 Sep30;8(3):128-39. eCollection 2016.
  30. Amiri F, Molaei S, Bahadori M, Nasiri F, Deyhim MR, Jalili MA, et al. Autophagy-modulated human bone marrow-derived mesenchymal stem cells accelerate liver restoration in mouse models of acute liver failure. Iran Biome J. 2016 Jul;20(3):135-44. doi: 10.7508/ibj.2016.03.002.
  31. Cavallari C, Fonsato V, Herrera MB, Bruno S, Tetta C, Camussi G. Role of lefty in the anti tumor activity of human adult liver stem cells. Oncogene. 2013 Feb;32(7):819-26. doi: 10.1038/onc.2012.114.
  32. Zhu X, He B, Zhou X, Ren J. Effects of transplanted bone-marrow-derived mesenchymal stem cells in animal models of acute hepatitis. Cell Tissue Res. 2013 Mar;351(3):477-86. doi: 10.1007/s00441-012-1524-3.
  33. Azandeh S, Gharravi AM, Orazizadeh M, Khodadi A, Tabar MH. Improvement of mesenchymal stem cell differentiation into the endoderm lineage by four step sequential method in biocompatible biomaterial. Bioimpacts. 2016 Mar; 6(1):9-13. doi: 10.15171/bi.2016.02.
  34. Deng Y, Zhang Y, Ye L, Zhang T, Cheng J, Chen G, et al. Umbilical cord-derived mesenchymal stem cells instruct monocytes towards an IL10-producing phenotype by secreting IL6 and HGF. Sci Rep. 2016 Dec;6:37566. doi: 10.1038/srep37566.
  35. Guo Y, Chen B, Chen LJ, Zhang CF, Xiang C. Current status and future prospects of mesenchymal stem cell therapy for liver fibrosis. J Zhejiang Univ Sci B. 2016 Nov;17(11):831-41.
  36. Winkler S, Hempel M, Bruckner S, Mallek F, Weise A; Liehr T, et al. Mouse white adipose tissue-derived mesenchymal stem cells gain pericentral and periportal hepatocyte features after differentiation in vitro, which are preserved in vivo after hepatic transplantation. Acta Physiol (Oxf). 2015 Oct;215(2):89-104. doi: 10.1111/apha.12560.
  37. Fu Y, Deng J, Jiang Q, Wang Y, Zhang Y, Yao Y, et al. Rapid generation of functional hepatocytelike cells from human adipose-derived stem cells. Stem Cell Res Ther. 2016 Aug;7(1):105. doi: 10.1186/s13287-016-0364-6.
  38. Terai S, Tsuchiya A. Status of and candidates for cell therapy in liver cirrhosis: overcoming the "point of no return" in advanced liver cirrhosis. J Gastroenterol. 2016 Sep 8. doi: 10.1007/s00535-016-1258-1.
  39. Tolosa L, Caron J, Hannoun Z, Antoni M, Lîpez S, Burks D, et al. Transplantation of hESC-derived hepatocytes protects mice from liver injury. Stem Cell Res Ther. 2015 Dec12;6:246. doi: 10.1186/s13287-015-0227-6.
  40. Zheng S, Yang J, Yang J, Tang Y, Shaî Q, Guo L, et al. Transplantation of umbilical cord mesenchymal stem cells via different routes in rats with acute liver failure. Int J Clin Exp Pathol. 2015 Dec;8(12):15854-62.
  41. Mubbacha F, Settmacherb U, Dirschc O, Xiea C, Dahmena U. Bioengineered livers: a new tool for drug testing and a promising solution to meet the growing demand for donor organs. Eur Surg Res. 2016 Jul;57(3-4):224-39. doi: 10.1159/000446211.
  42. Dolgikh MS. Klinicheskii opyt transplantatsii gepatotsitov dlia lecheniia pechenochnoi nedostatochnosti [Clinical experience. Hepatocyte transplantation for the treatment of liver failure]. Klin Meditsina. 2012;(4):18-22.
  43. Nagamoto Y, Takayama K, Ohashi K, Okamoto R, Sakurai F, Tachibana M, et al. Transplantation of a human iPSC-derived hepatocyte sheet increases survival in mice with acute liver failure. J Hepatol. 2016 Jan-May;64(5):1068-75. doi: 10.1016/j.jhep.2016.01.004.
  44. Ivanov DV, Riazanov AI, Khadartsev AA. Transplantatsiia gepatotsitov v lechenii zabolevanii pecheni – nastoiashchee i budushchee [Transplantation of hepatocytes in the treatment of liver diseases - Present and Future]. Vest Novykh Med Tekhnologii. 2006;XIII(3):39-44.
  45. Liu Y, Yang X, Jing Y, Zhang S , Zong C, Jiang J, et al. Contribution and mobilization of mesenchymal stem cells in a mouse model of carbon tetrachloride-induced liver fibrosis. Sci Reð. 2015 Dec 8;5:17762. doi: 10.1038/srep17762.
  46. Vosough M, Moossavi S, Mardpour S, Akhlaghpoor S, Azimian V, Jarughi N, et al. Repeated intraportal injection of mesenchymal stem cells in combination with pioglitazone in patients with compensated cirrhosis: a clinical report of two cases. Arch Iran Med. 2016 Feb;19(2):131-36. doi: 0161902/AIM.0011.
  47. Lee SC, Jeong HJ, Lee SK, Kim SJ. Lipopolysaccharide preconditioning of adipose-derived stem cells improves liver-regenerating activity of the secretome. Stem Cell Res Ther. 2015 Apr14;6:75. doi: 10.1186/s13287-015-0072-7.
  48. Kochat V, Baligar P, Maiwall R, Mukhopadhyay A. Bone marrow stem-cell therapy for genetic and chronic liver diseases. Hepatol Int. 2014 Apr;8(2):166-78. doi: 10.1007/s12072-013-9499-z.
  49. Chang N, Ge J, Xiu L, Zhao Z, Duan X, Tian L, et al. HuR mediates motility of human bone marrow-derived mesenchymal stem cells triggered by sphingosine 1-phosphate in liver fibrosis. J Mol Med (Berl). 2016 Aug. doi: 10.1007/s00109-016-1460-x.
  50. Tan CY, Lai RC, Wong W, Dan YY, Lim SK, Ho HK. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther. 2014 Jun10;5(3):76. doi: 10.1186/scrt465.
  51. Sergeeva AS, Pivovarov IuI, Kuril'skaia TE, Runovich AA. Kletochnaia terapiia v lechenii pechenochnoi nedostatochnosti [Cell therapy in the treatment of liver failure]. Biul VSNTs SO RAMN. 2005;(7):119-24.
  52. Poveshchenko AF, Poveshchenko OV, Konenkov VI. Sovremennye dostizheniia v sozdanii metodov izucheniia migratsii stvolovykh kletok [Recent advances in the creation of the methods for studying stem cells migration]. Vestn RAMN. 2013;(9):46-51.
  53. Zhou P, Wirthlin L, McGee J, Annett G, Nolta J. Contribution of human hematopoie tic stem cells to liver repair. Semin Immunopathol. 2009 Sep;31(3):411-19. doi: 10.1007/s00281-009-0166-3.
    54.Cen P, Chen J, Nu C, Fan L, Wang J, Li L. Noninvasive in-vivo tracing and imaging of transplanted stem cells for liver regeneration. Stem Cell Res Ther. 2016 Sep;7(1):143. doi: 10.1186/s13287-016-0396-y.
Address for correspondence:
210023, Republic of Belarus,
Vitebsk, Frunze pr., 27,
EE "Vitebsk State Medical University",
Department of histology, cytology and embryology.
Tel.: 375 33 675 76 99
Tel.: 8 0212 60-29-14
E-mail: lebedeva.ya-elenale2013@yandex.ru
Elena I. Lebedeva
Information about the authors:
Shchastny A.T. MD, Professor, Rector, EE "Vitebsk State Medical University".
Sushkou S.A. PhD, Ass. Professor, Vice-rector (Science), EE "Vitebsk State Medical University".
Myadelets O.D. MD, Professor, Head of department of histology, cytology and embryology, EE "Vitebsk State Medical University".
Lebedeva E.I. PhD, Assistant of the department of histology, cytology and embryology, EE "Vitebsk State Medical University".
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