Effect of mesenchymal stem cell in liver regeneration and clinical applications

Abstract

Liver disease accounts for approximately 2 million deaths per year worldwide with cirrhosis, viral hepatitis, and malignancy being the most common causes. Consequently, the regenerative capacity of the liver is a topic of extreme interest in the search for curative therapies to end-stage liver disease. Mesenchymal stem cells (MSCs) have emerged as a promising new therapy for hepatic regeneration. MSCs have multiple properties that make them an appropriate treatment option for liver disease including easy accessibility, targeted migration, immunomodulatory potential and antifibrotic/antioxidant effects. Additionally, MSCs have potential clinical applications in acellular therapy and tissue engineering. Liver regeneration with concurrent attenuation of liver injury makes MSCs a compelling therapeutic target in the setting of severe liver disease. This review outlines the mechanisms of MSC-driven liver regeneration and suggests potential clinical applications.

Keywords

Mesenchymal stem cell / liver regeneration / end-stage liver disease

References

[1] Perugorria MJ,Banales JM.Cholangiocyte-to-hepatocyte differentiation: a context - dependent process and an opportunity for regenerative medicine.Hepatology2019;69:480-3

[2] Michalopoulos GK.Principles of liver regeneration and growth homeostasis.Compr Physiol2013;3:485-513

[3] Fujii H,Oe S.Contribution of bone marrow cells to liver regeneration after partial hepatectomy in mice.J Hepatol2002;36:653-659

[4] Michalopoulos GK.Liver stem cells: experimental findings and implications for human liver disease.Gastroenterology2015;149:876-82 PMCID:PMC4584191

[5] Jiang JX.Liver injury and the activation of the hepatic myofibroblasts.Curr Pathobiol Rep2013;1:215-23 PMCID:PMC3748972

[6] Cordero-Espinoza L.The balancing act of the liver: tissue regeneration versus fibrosis.J Clin Invest2018;128:85-96 PMCID:PMC5749503

[7] Xu J.Bone marrow-derived fibrocytes contribute to liver fibrosis.Exp Biol Med2015;240:691-700 PMCID:PMC4866973

[8] Bellini A.The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses.Lab Invest2007;87:858-70

[9] Ling C,Rolfs Z,Frey BL.Differentiated fibrocytes assume a functional mesenchymal phenotype with regenerative potential.Sci Adv2019;5:eaav7384 PMCID:PMC6506241

[10] Markets R and. Global Organ Transplantation Market Review 2014-2019 - Forecast to 2024. Available from: https://www.prnewswire.com/news-releases/global-organ-transplantation-market-review-2014-2019---forecast-to-2024-300952739.html. [Last accessed on 20 Apr 2021]

[11] Lange C,Lioznov M-V.Liver-specific gene expression in mesenchymal stem cells is induced by liver cells.World J Gastroenterol2005;11:4497-504 PMCID:PMC4398698

[12] Ong S-Y,Leong KW.Inducing hepatic differentiation of human mesenchymal stem cells in pellet culture.Biomaterials2006;27:4087-97

[13] Campagnoli C,Kumar S,Bellantuono I.Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow.Blood2001;98:2396-402

[14] De Ugarte DA,Elbarbary A.Comparison of multi-lineage cells from human adipose tissue and bone marrow.Cells Tissues Organs2003;174:101-9

[15] Erices A,Minguell JJ.Mesenchymal progenitor cells in human umbilical cord blood.Br J Haematol2000;109:235-42

[16] Jiang Y,Lenvik T,Reyes M.Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain.Exp Hematol2002;30:896-904

[17] Zvaifler NJ,Adams G.Mesenchymal precursor cells in the blood of normal individuals.Arthritis Res2000;2:477-88 PMCID:PMC17820

[18] Bernardo ME,Pagliara D.Ex vivo expansion of mesenchymal stromal cells.Best Pract Res Clin Haematol2011;24:73-81

[19] Chapel A,Bensidhoum M.Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome.J Gene Med2003;5:1028-38

[20] Eom YW,Baik SK.Mesenchymal stem cell therapy for liver fibrosis.Korean J Intern Med2015;30:580-9 PMCID:PMC4578027

[21] Forbes SJ,Dhawan A.Cell therapy for liver disease: From liver transplantation to cell factory.J Hepatol2015;62:S157-69

[22] Av P.Expression of early hematopoietic markers in cord blood and mobilized blood.Tsitologiia2012;54:774-82

[23] Martinez-Agosto JA,Hartenstein V.The hematopoietic stem cell and its niche: a comparative view.Genes Dev2007;21:3044-3060

[24] Mizukoshi E.Immune cell therapy for hepatocellular carcinoma.J Hematol Oncol2019;12:52 PMCID:PMC6542133

[25] Asahara T,Sullivan A.Isolation of putative progenitor endothelial cells for angiogenesis.Science1997;275:964-6

[26] Kaushal S,Guleserian KJ.Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo.Nat Med2001;7:1035-40 PMCID:PMC2818999

[27] El-Ansary M,Mogawer S.Phase II trial: undifferentiated versus differentiated autologous mesenchymal stem cells transplantation in Egyptian patients with HCV induced liver cirrhosis.Stem Cell Rev Rep2012;8:972-81

[28] Satija NK,Verma YK.Mesenchymal stem cell-based therapy: a new paradigm in regenerative medicine.J Cell Mol Med2009;13:4385-402 PMCID:PMC4515054

[29] Dominici M,Mueller I.Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.Cytotherapy2006;8:315-7

[30] Huang L,Gu J.A randomized, placebo-controlled trial of human umbilical cord blood mesenchymal stem cell infusion for children with cerebral palsy.Cell Transplant2018;27:325-34 PMCID:PMC5898688

[31] Chamberlain G,Ashton B.Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing.Stem Cell2007;25:2739-49

[32] Sordi V,Marchesi F.Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets.Blood2005;106:419-27

[33] Ullah M,Thakor AS.Mesenchymal stromal cell homing: mechanisms and strategies for improvement.iScience2019;15:421-38 PMCID:PMC6529790

[34] Xiang G,Fang C,Chen K.A preliminary study of the homing capacity of allograft mesenchymal stem cells to rat liver.Di Yi Jun Yi Da Xue Xue Bao2005;25:994-7

[35] Gao J,Muzic RF,Caplan AI.The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion.Cells Tissues Organs169:12-20

[36] Wojakowski W,Michałowska A.Mobilization of CD34/CXCR4+, CD34/CD117+, c-met+ stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction.Circulation2004;110:3213-20

[37] Bowie MB,Kent DG,Hoodless PA.Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect.J Clin Invest2006;116:2808-16 PMCID:PMC1578623

[38] Gordon MY,Pai M.Characterization and clinical application of human CD34+ stem/progenitor cell populations mobilized into the blood by granulocyte colony-stimulating factor.Stem Cells2006;24:1822-30

[39] Kollet O,Chen Y-Q.HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver.J Clin Invest2003;112:160-9 PMCID:PMC164291

[40] Jin DK,Kopp H-G.Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes.Nat Med2006;12:557-67 PMCID:PMC2754288

[41] Petit I,Rafii S.The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis.Trends Immunol2007;28:299-307 PMCID:PMC2952492

[42] Tang YL,Cheng M.Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression.Circ Res2009;104:1209-16 PMCID:PMC2756190

[43] Horuk R.Chemokines beyond inflammation.Nature1998;393:524-5

[44] Kahn J,Jansson-Sjostrand L.Overexpression of CXCR4 on human CD34+ progenitors increases their proliferation, migration, and NOD/SCID repopulation.Blood2004;103:2942-9

[45] Liu H,Li Y.The role of SDF-1-CXCR4/CXCR7 axis in the therapeutic effects of hypoxia-preconditioned mesenchymal stem cells for renal ischemia/reperfusion injury.PloS One2012;7:e34608 PMCID:PMC3325280

[46] Zhang D,Zhou X.Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium.J Mol Cell Cardiol2008;44:281-92 PMCID:PMC2601571

[47] Lei Y,Han Q,Zhang L.G-CSF enhanced SDF-1 gradient between bone marrow and liver associated with mobilization of peripheral blood CD34+ cells in rats with acute liver failure.Dig Dis Sci2010;55:285-91

[48] Ma HC,Ren HZ,Ding YT.Targeted migration of mesenchymal stem cells modified with CXCR4 to acute failing liver improves liver regeneration.World J Gastroenterol2014;20:14884-94 PMCID:PMC4209551

[49] Wynn RF,Corradi-Perini C.A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow.Blood2004;104:2643-5

[50] Du Z,Yan J.Mesenchymal stem cells overexpressing C-X-C chemokine receptor type 4 improve early liver regeneration of small-for-size liver grafts.Liver Transpl2013;19:215-25

[51] Schwartz RE,Koodie L.Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells.J Clin Invest2002;109:1291-302 PMCID:PMC150983

[52] Zhang GZ,Zheng LB,Zhang XL.In vivo hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells: therapeutic effect on liver fibrosis/cirrhosis.World J Gastroenterol2017;23:8152-68 PMCID:PMC5739922

[53] Sato Y,Kato J.Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion.Blood2005;106:756-63

[54] Dai LJ,Guan LX,Zhou JX.The therapeutic potential of bone marrow-derived mesenchymal stem cells on hepatic cirrhosis.Stem Cell Res2009;2:16-25

[55] Yan Y,Qian H.Mesenchymal stem cells from human umbilical cords ameliorate mouse hepatic injury in vivo.Liver Int2009;29:356-65

[56] Jang YY,Baylin SB,Sharkis SJ.Hematopoietic stem cells convert into liver cells within days without fusion.Nat Cell Biol2004;6:532-9

[57] Chen L,Chen L.Human menstrual blood-derived stem cells ameliorate liver fibrosis in mice by targeting hepatic stellate cells via paracrine mediators.STEM CELLS Transl Med2017;6:272-84 PMCID:PMC5442725

[58] Skalnikova H. Proteomic techniques for characterisation of mesenchymal stem cell secretome.Biochimie2013;95:2196-211

[59] Wang J,Liao L.Inhibition of hepatic stellate cells proliferation by mesenchymal stem cells and the possible mechanisms.Hepatol Res2009;39:1219-28

[60] Rabani V,Gharavi M,Azhdari Z.Mesenchymal stem cell infusion therapy in a carbon tetrachloride-induced liver fibrosis model affects matrix metalloproteinase expression.Cell Biol Int2010;34:601-5

[61] Sakaida I,Yamamoto N.Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice.Hepatology2004;40:1304-11

[62] Wang L,Wang L.Hepatic vascular endothelial growth factor regulates recruitment of rat liver sinusoidal endothelial cell progenitor cells.Gastroenterology2012;143:1555-63.e2 PMCID:PMC3505224

[63] Kim SU,Wanless IR,Han K-H.The Laennec staging system for histological sub-classification of cirrhosis is useful for stratification of prognosis in patients with liver cirrhosis.J Hepatol2012;57:556-63

[64] Gorji S, Karimpor Malekshah AA, Hashemi-Soteh MB, Rafiei A, Parivar K, Aghdami N. Effect of mesenchymal stem cells on Doxorubicin-induced fibrosis.Cell J2012;14:142-51 PMCID:PMC3584430

[65] Zhang D,Miao D.Transplanted human amniotic membrane-derived mesenchymal stem cells ameliorate carbon tetrachloride-induced liver cirrhosis in mouse.PloS One2011;6:e16789 PMCID:PMC3033905

[66] Michalopoulos GK.Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas.Am J Pathol2010;176:2-13 PMCID:PMC2797862

[67] Marsden ER,Fujio K,Thorgeirsson SS.Expression of acidic fibroblast growth factor in regenerating liver and during hepatic differentiation.Lab Invest1992;67:427-33

[68] Webber EM,Fausto N.In vivo response of hepatocytes to growth factors requires an initial priming stimulus.Hepatology1994;19:489-97

[69] Nozawa K,Yamamoto A,Suzuki M.Up-regulation of telomerase in primary cultured rat hepatocytes.J Biochem1999;126:361-7

[70] Li W-L,Yao Y-C.Isolation and characterization of bipotent liver progenitor cells from adult mouse.Stem Cells2006;24:322-32

[71] Wang J,Chen J.Role of mesenchymal stem cells, their derived factors, and extracellular vesicles in liver failure.Stem Cell Res Ther2017;8:137 PMCID:PMC5460333

[72] Tan CY,Wong W,Lim S-K.Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models.Stem Cell Res Ther2014;5:76 PMCID:PMC4229780

[73] Li T,Wang B.Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis.Stem Cells Dev2012;22:845-54 PMCID:PMC3585469

[74] Robbins PD.Regulation of immune responses by extracellular vesicles.Nat Rev Immunol2014;14:195-208 PMCID:PMC4350779

[75] Zhang B,Lai RC,Choo ABH.Mesenchymal stem cells secrete immunologically active exosomes.Stem Cells Dev2014;23:1233-44

[76] Weiss ARR.Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs.Front Immunol2019;10:1191 PMCID:PMC6557979

[77] De Miguel MP,Blázquez-Martínez A.Immunosuppressive properties of mesenchymal stem cells: advances and applications.Curr Mol Med2012;12:574-91

[78] Sato K,Oh I.Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells.Blood2007;109:228-34

[79] Wang D,DuBois RN.The role of prostaglandins and other eicosanoids in the gastrointestinal tract.Gastroenterology2005;128:1445-61

[80] Breyer RM,Myers SA.Prostanoid receptors: subtypes and signaling.Annu Rev Pharmacol Toxicol2001;41:661-90

[81] Samuelsson B,Jakobsson PJ.Membrane prostaglandin E synthase-1: a novel therapeutic target.Pharmacol Rev2007;59:207-24

[82] Spaggiari GM,Becchetti F.MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2.Blood2009;113:6576-83

[83] Linnemeyer PA.Prostaglandin E2-induced changes in the phenotype, morphology, and lytic activity of IL-2-activated natural killer cells.J Immunol1993;150:3747-54

[84] Yakar I,Shakhar G.Prostaglandin e(2) suppresses NK activity in vivo and promotes postoperative tumor metastasis in rats.Ann Surg Oncol2003;10:469-79

[85] Wang X,Akkari Y.Cell fusion is the principal source of bone-marrow-derived hepatocytes.Nature2003;422:897-901

[86] Volarevic V,Arsenijevic N,Lukic ML.Interleukin-1 receptor antagonist (IL-1Ra) and IL-1Ra producing mesenchymal stem cells as modulators of diabetogenesis.Autoimmunity2010;43:255-63

[87] Parekkadan B,Suganuma K.Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure.PloS One2007;2:e941 PMCID:PMC1978513

[88] Djouad F,Bouffi C.Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism.Stem Cells2007;25:2025-32

[89] Jiang X-X,Liu B.Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells.Blood2005;105:4120-6

[90] Usunier B,Tamarat R.Management of fibrosis: the mesenchymal stromal cells breakthrough.Stem Cells Int2014;2014:340257 PMCID:PMC4123563

[91] Semedo P,Antonio Cenedeze M.Mesenchymal stem cells attenuate renal fibrosis through immune modulation and remodeling properties in a rat remnant kidney model.Stem Cells2009;27:3063-73

[92] Wu Y,Enhe J.Bone marrow-derived mesenchymal stem cell attenuates skin fibrosis development in mice.Int Wound J2014;11:701-10

[93] Ali G,Khan M.Nitric oxide augments mesenchymal stem cell ability to repair liver fibrosis.J Transl Med2012;10:75 PMCID:PMC3419634

[94] Chen S,Lin N,Hu K.Activation of Notch1 signaling by marrow-derived mesenchymal stem cells through cell-cell contact inhibits proliferation of hepatic stellate cells.Life Sci2011;89:975-81

[95] Parekkadan B,Megeed Z.Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells.Biochem Biophys Res Commun2007;363:247-52 PMCID:PMC2096777

[96] Lin N,Chen S.Nerve growth factor-mediated paracrine regulation of hepatic stellate cells by multipotent mesenchymal stromal cells.Life Sci2009;85:291-5

[97] Duman DG,Ugurlu MU.Mesenchymal stem cells suppress hepatic fibrosis accompanied by expanded intrahepatic natural killer cells in rat fibrosis model.Mol Biol Rep2019;46:2997-3008

[98] Gao B.Natural killer and natural killer T cells in liver fibrosis.Biochim Biophys Acta2013;1832:1061-9 PMCID:PMC3552008

[99] Singer NG.Mesenchymal stem cells: mechanisms of inflammation.Annu Rev Pathol2011;6:457-78

[100] Clément S,Negro F.Hepatitis C virus infection: molecular pathways to steatosis, insulin resistance and oxidative stress.Viruses2009;1:126-43 PMCID:PMC3185489

[101] Tanikawa K.Studies on oxidative stress in liver diseases: important future trends in liver research.Med Mol Morphol2006;39:22-7

[102] Ivanov AV,Ivanova ON,Kochetkov SN.Hepatitis C virus proteins activate NRF2/ARE pathway by distinct ROS-dependent and independent mechanisms in HUH7 cells.PloS One2011;6:e24957 PMCID:PMC3172309

[103] Zhu R,Zhang L.Oxidative stress and liver disease.Hepatol Res2012;42:741-9

[104] Cash WJ,Young IS.Primary biliary cirrhosis is associated with oxidative stress and endothelial dysfunction but not increased cardiovascular risk.Hepatol Res2010;40:1098-106

[105] Cho K-A,Seoh J-Y,Ryu K-H.Mesenchymal stem cells restore CCl4-induced liver injury by an antioxidative process.Cell Biol Int2012;36:1267-74

[106] Parola M.Oxidative stress-related molecules and liver fibrosis.J Hepatol2001;35:297-306

[107] Quintanilha LF,Hirose Y.Canine mesenchymal stem cells show antioxidant properties against thioacetamide-induced liver injury in vitro and in vivo.Hepatol Res2014;44:E206-17

[108] Ayatollahi M,Jamshidzadeh A.Antioxidant effects of bone marrow mesenchymal stem cell against carbon tetrachloride-induced oxidative damage in rat livers.Int J Organ Transplant Med2014;5:166-73 PMCID:PMC4243048

[109] Ledda-Columbano GM,Curto M.Induction of two different modes of cell death, apoptosis and necrosis, in rat liver after a single dose of thioacetamide.Am J Pathol1991;139:1099-109 PMCID:PMC1886348

[110] Li X,Alexander B.Reproducible production of thioacetamide-induced macronodular cirrhosis in the rat with no mortality.J Hepatol2002;36:488-93

[111] Weber LWD,Stampfl A.Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model.Crit Rev Toxicol2003;33:105-36

[112] Joyeux M,Fleurentin J,Dorfman P.tert-Butyl hydroperoxide-induced injury in isolated rat hepatocytes: a model for studying anti-hepatotoxic crude drugs.Planta Med1990;56:171-4

[113] Devasagayam TPA,Boloor KK,Ghaskadbi SS.Free radicals and antioxidants in human health: current status and future prospects.J Assoc Physicians India2004;52:794-804

[114] Dey R,Gray E,Scolding N.Human mesenchymal stem cells increase anti-oxidant defences in cells derived from patients with Friedreich’s ataxia.Cerebellum2012;11:861-71

[115] Kharaziha P,Noorinayer B.Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I–II clinical trial.Eur J Gastroenterol Hepatol2009;21:1199-205

[116] Jang YO,Baik SK.Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study.Liver Int2014;34:33-41

[117] Suk KT,Kim MY.Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial.Hepatology2016;64:2185-97

[118] Alimoghaddam K,Bonab MM.106: Phase 1 Trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis.Biol Blood Marrow Transplant2008;14:41

[119] Liver Diseases and Mesenchymal Stem Cells - List Results. Home - ClinicalTrials.gov, US National Library of Medicine, NIH. Available from: clinicaltrials.gov/ct2/results?cond=Liver+Diseases. [Last accessed on 12 Jul 2021]

[120] Amer M-EM,El-Kheir WA.Clinical and laboratory evaluation of patients with end-stage liver cell failure injected with bone marrow-derived hepatocyte-like cells.Eur J Gastroenterol Hepatol2011;23:936-41

[121] Xue H-L,Wu X-L.Clinical therapeutic effects of human umbilical cord-derived mesenchymal stem cells transplantation in the treatment of end-stage liver disease.Transplant Proc2015;47:412-8

[122] PT. Prodia Stem Cell Indonesia. Umbilical Cord Mesenchymal Stem Cell for Liver Cirrhosis Patient Caused by Hepatitis B: Phase I/ II Study. clinicaltrials.gov; 2020. Available from: https://clinicaltrials.gov/ct2/show/NCT04357600. [Last accessed on 20 Apr 2021]

[123] Kantarcioglu M. Efficacy of Exvivo Expanded Autologous Mesenchymal Stem Cell Transplantation Via Peripheral Vein in Patients With Liver Cirrhosis. clinicaltrials.gov; 2012. Available from: https://clinicaltrials.gov/ct2/show/NCT01499459. [Last accessed on 20 Apr 2021]

[124] Mohamadnejad M,Bagheri M.Randomized placebo-controlled trial of mesenchymal stem cell transplantation in decompensated cirrhosis.Liver Int2013;33:1490-6

[125] Yu SJ,Lyu S.Safety and efficacy of human umbilical cord derived-mesenchymal stem cell transplantation for treating patients with HBV-related decompensated cirrhosis.Zhonghua Gan Zang Bing Za Zhi2016;24:51-5

[126] Sakai Y,Seki A.Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell.Regen Ther2017;6:52-64 PMCID:PMC6134901

[127] Friedenstein AJ,Lalykina KS.The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells.Cell Prolif1970;3:393-403

[128] Yang X,Han Z,Wei L.Mesenchymal stem cell therapy for liver disease: full of chances and challenges.Cell Biosci2020;10:123 PMCID:PMC7590738

[129] Batsali AK,Papadaki HA.Mesenchymal stem cells derived from Wharton’s jelly of the umbilical cord: biological properties and emerging clinical applications.Curr Stem Cell Res2013;8:144-55

[130] Mueller SM.Age-related decline in the osteogenic potential of human bone marrow cells cultured in three-dimensional collagen sponges.J Cell Biochem2001;82:583-90

[131] Lu LL,Yang SG.Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials.Haematologica2006;91:1017-26

[132] Hsieh J-Y,Chang S-J,Wang H-W.Functional module analysis reveals differential osteogenic and stemness potentials in human mesenchymal stem cells from bone marrow and Wharton’s jelly of umbilical cord.Stem Cells Dev2010;19:1895-910

[133] Cho PS,Hirsh EL.Immunogenicity of umbilical cord tissue derived cells.Blood2008;111:430-8

[134] Deuse T,Tang-Quan K.Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells.Cell Transplant2011;20:655-67

[135] Eggenhofer E,Kroemer A.Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion.Front Immunol2012;3:297 PMCID:PMC3458305

[136] Higashimoto M,Takamura M.Adipose tissue derived stromal stem cell therapy in murine ConA-derived hepatitis is dependent on myeloid-lineage and CD4+ T-cell suppression.Eur J Immunol2013;43:2956-68

[137] Cao H,Yu J.Therapeutic potential of transplanted placental mesenchymal stem cells in treating Chinese miniature pigs with acute liver failure.BMC Med2012;10:56 PMCID:PMC3386887

[138] Li J,Xin J.Immediate intraportal transplantation of human bone marrow mesenchymal stem cells prevents death from fulminant hepatic failure in pigs.Hepatology2012;56:1044-52

[139] Amin MA,Rashed LA.Short-term evaluation of autologous transplantation of bone marrow-derived mesenchymal stem cells in patients with cirrhosis: Egyptian study.Clin Transplant2013;27:607-12

[140] Baertschiger RM,Morel P.Fibrogenic potential of human multipotent mesenchymal stromal cells in injured liver.PloS One2009;4:e6657 PMCID:PMC2722022

[141] di Bonzo LV,Cravanzola C.Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: engraftment and hepatocyte differentiation versus profibrogenic potential.Gut2008;57:223-31

[142] Krampera M,Angeli R.Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells.Stem Cells2006;24:386-98

[143] Linero I.Paracrine effect of mesenchymal stem cells derived from human adipose tissue in bone regeneration.PLoS One2014;9:e107001 PMCID:PMC4157844

[144] Giuliani M,Nanbakhsh A.TLR ligands stimulation protects MSC from NK killing.Stem Cells2014;32:290-300

[145] Kang SH,Eom YW.Mesenchymal stem cells for the treatment of liver disease: present and perspectives.Gut Liver2020;14:306-15 PMCID:PMC7234888

[146] Liu Y,Xing F.Precise regulation of miR-210 is critical for the cellular homeostasis maintenance and transplantation efficacy enhancement of mesenchymal stem cells in acute liver failure therapy.Cell Transplant2017;9:805-20 PMCID:PMC5657719

[147] Bruno S,Deregibus MC,Tetta C.Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth.Stem Cells Dev2013;22:758-71

[148] Studeny M,Champlin RE,Fidler IJ.Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors.Cancer Res2002;62:3603-8

[149] Xie C,Lin BL.Interferon- β gene-modified human bone marrow mesenchymal stem cells attenuate hepatocellular carcinoma through inhibiting AKT/FOXO3a pathway.Br J Cancer2013;109:1198-205 PMCID:PMC3778282

[150] Su Y,Zhang J.Interferon-α2b gene-modified human bone marrow mesenchymal stem cells inhibit hepatocellular carcinoma by reducing the Notch1 levels.Life Sci2015;143:18-26

[151] Sun XY,Qin K.MSC (TRAIL)-mediated HepG2 cell death in direct and indirect co-cultures.Anticancer Res2011;31:3705-12

[152] Zhang B,Li D,Zhu KS.The inhibitory effect of MSCs expressing TRAIL as a cellular delivery vehicle in combination with cisplatin on hepatocellular carcinoma.Cancer Biol Ther2012;13:1175-84 PMCID:PMC3469475

[153] Chen X,Zhao X.Prophylaxis against carcinogenesis in three kinds of unestablished tumor models via IL12-gene-engineered MSCs.Carcinogenesis2006;27:2434-41.

[154] Lai RC,Tan KH.Exosomes for drug delivery - a novel application for the mesenchymal stem cell.Biotechnol Adv2013;31:543-51

[155] Kang K,Cai W.Exosomes secreted from CXCR4 overexpressing mesenchymal stem cells promote cardioprotection via Akt signaling pathway following myocardial infarction.Stem Cells Int2015;2015:659890 PMCID:PMC4436515

[156] Mirotsou M,Deb A.Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair.Proc Natl Acad Sci U S A2007;104:1643-8 PMCID:PMC1785280

[157] Wang X,Huang W.Hsp20-engineered mesenchymal stem cells are resistant to oxidative stress via enhanced activation of Akt and increased secretion of growth factors.Stem Cells2009;27:3021-31 PMCID:PMC2806498

[158] Herberg S,Johnson MH,Isales CM.Stromal cell-derived factor-1β mediates cell survival through enhancing autophagy in bone marrow-derived mesenchymal stem cells.PloS One2013;8:e58207 PMCID:PMC3589360

[159] Semenza GL.Hypoxia-inducible factor 1: control of oxygen homeostasis in health and disease.Pediatr Res2001;49:614-7

[160] Song H,Lim S.Transfection of mesenchymal stem cells with the FGF-2 gene improves their survival under hypoxic conditions.Mol Cells2005;19:402-7

[161] Liu N,Zhang J.CXCR4-overexpressing bone marrow-derived mesenchymal stem cells improve repair of acute kidney injury.Am J Physiol Renal Physiol2013;305:F1064-73

[162] Nakamura Y,Kawai K,Suzuki S.Enhanced wound healing by topical administration of mesenchymal stem cells transfected with stromal cell-derived factor-1.Biomaterials2013;34:9393-400

[163] Jang YO,Yun C-O.Effect of function-enhanced mesenchymal stem cells infected with decorin-expressing adenovirus on hepatic fibrosis.Stem Cells Transl Med2016;5:1247-56 PMCID:PMC4996441

[164] Sun C,Chen YW.Transplantation of urokinase-type plasminogen activator gene-modified bone marrow-derived liver stem cells reduces liver fibrosis in rats.J Gene Med2008;10:855-66

[165] Lan L,Sun C,Hu J.Transplantation of bone marrow-derived hepatocyte stem cells transduced with adenovirus-mediated IL-10 gene reverses liver fibrosis in rats.Transpl Int2008;21:581-92

[166] Ji R,You N.The differentiation of MSCs into functional hepatocyte-like cells in a liver biomatrix scaffold and their transplantation into liver-fibrotic mice.Biomaterials2012;33:8995-9008

[167] Mazzocchi A,Huntwork R,Skardal A.Optimization of collagen type I-hyaluronan hybrid bioink for 3D bioprinted liver microenvironments.Biofabrication2018;11:015003 PMCID:PMC8008502

[168] Skardal A,Bharadwaj S,Soker S.Tissue specific synthetic ECM hydrogels for 3-D in vitro maintenance of hepatocyte function.Biomaterials2012;33:4565-75 PMCID:PMC3719050

[169] Rashidi H,Szkolnicka D,Hay DC.Fluid shear stress modulation of hepatocyte-like cell function.Arch Toxicol2016;90:1757-61 PMCID:PMC4894932

[170] Gieseck RL 3rd,Bort R.Maturation of induced pluripotent stem cell derived hepatocytes by 3D-culture.PLoS One2014;9:e86372 PMCID:PMC3899231

[171] Wang Y,Deng P.In situ differentiation and generation of functional liver organoids from human iPSCs in a 3D perfusable chip system.Lab Chip2018;18:3606-16

[172] Hu H,Artegiani B.Long-term expansion of functional mouse and human hepatocytes as 3D organoids.Cell2018;175:1591-1606.e19

[173] Arufe MC,Fuentes-Boquete I,Blanco FJ.Differentiation of synovial CD-105(+) human mesenchymal stem cells into chondrocyte-like cells through spheroid formation.J Cell Biochem2009;108:145-55

[174] Zhang X,Pan K,Liu R.3D spheroid culture enhances the expression of antifibrotic factors in human adipose-derived MSCs and improves their therapeutic effects on hepatic fibrosis.Stem Cells Int2016;2016:4626073 PMCID:PMC4789048

[175] Uygun BE,Yagi H.Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix.Nat Med2010;16:814-20 PMCID:PMC2930603

[176] Wu F,Ren Y.Generation of hepatobiliary organoids from human induced pluripotent stem cells.J Hepatol2019;70:1145-58

[177] Katsuda T,Sakai Y.Generation of hepatic organoids with biliary structures. In: Tanimizu N, editor. Hepatic Stem Cells. New York: Springer; 2019. pp. 175-85.

[178] Takebe T,Koike H.Generation of a vascularized and functional human liver from an iPSC-derived organ bud transplant.Nat Protoc2014;9:396-409

[179] Nie YZ,Ogawa M,Taniguchi H.Human liver organoids generated with single donor-derived multiple cells rescue mice from acute liver failure.Stem Cell Res Ther2018;9:5 PMCID:PMC5763644

[180] Studeny M,Dembinski JL.Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents.J Natl Cancer Inst2004;96:1593-1603

[181] Rhee KJ,Eom YW.Mesenchymal stem cell-mediated effects of tumor support or suppression.Int J Mol Sci2015;16:30015-33 PMCID:PMC4691158

[182] Hanahan D.Hallmarks of cancer: the next generation.Cell2011;144:646-74.

[183] Orimo A,Sgroi DC.Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.Cell2005;121:335-48

[184] Hung SC,Chen SC,Prockop DJ.Angiogenic effects of human multipotent stromal cell conditioned medium activate the PI3K-Akt pathway in hypoxic endothelial cells to inhibit apoptosis, increase survival, and stimulate angiogenesis.Stem Cells2007;25:2363-70

[185] Hung SC,Hsu SC.Short-term exposure of multipotent stromal cells to low oxygen increases their expression of CX3CR1 and CXCR4 and their engraftment in vivo.PloS One2007;2:e416 PMCID:PMC1855077

[186] Crisostomo PR,Markel TA,Lahm T.Human mesenchymal stem cells stimulated by TNF-alpha, LPS, or hypoxia produce growth factors by an NF kappa B- but not JNK-dependent mechanism.Am J Physiol Cell Physiol2008;294:C675-82

[187] Dias S,Lam G.VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition.Blood2002;99:2532-40