Beyond fibrosis: stellate cells as liver stem cells

Abstract

The high regenerative potential of the liver is driven by parenchymal and non-parenchymal cells, which restore the original liver mass after injury by cell proliferation. The contribution of stem- and progenitor cells to liver regeneration is mainly observed when hepatocyte proliferation is impaired. However, the origin of stem/progenitor cells and their effectivity to restore injured liver is currently discussed controversially. Hepatic stellate cells, which are mainly known for their contribution to fibrosis in chronic liver diseases, were recently identified as mesenchymal stem cells (MSC) of the liver. Stellate cells are also involved in liver regeneration and fulfill a dual function by supporting neighboring cells and developing into liver epithelial cells. This demonstrates that stellate cells not only exhibit the same expression profile and differentiation potential but also functional similarities to MSC of other organs, which are at present intensively studied by many groups for their therapeutic use in liver diseases.

Zusammenfassung

Die sehr gute Fähigkeit der Leber zur Regeneration wird von Parenchym- und Nicht-Parenchymzellen getragen, die nach einer Schädigung die ursprüngliche Lebermasse durch Zellteilung wiederherstellen. Eine Beteiligung von Stamm- und Progenitorzellen an regenerativen Prozessen der Leber wird v. a. bei einer inhibierten Proliferation von Hepatozyten beobachtet. Die Herkunft der Stamm-/Progenitorzellen und das Ausmaß ihrer Beteiligung an der Regeneration wird jedoch derzeit kontrovers diskutiert. Hepatische Sternzellen, die hauptsächlich durch ihre Beteiligung an der Entstehung einer Fibrose bei chronischen Erkrankungen der Leber bekannt sind, wurden kürzlich als mesenchymale Stammzellen (MSC) der Leber identifiziert. Sternzellen sind ebenfalls in die Regeneration der geschädigten Leber involviert und besitzen offensichtlich eine duale Funktion, indem sie einerseits benachbarte Zellen beeinflussen und andererseits epitheliale Zellen der Leber bilden können. Damit zeigen Sternzellen nicht nur ein Expressionsprofil und Differenzierungspotenzial, sondern auch funktionell eine hohe Übereinstimmung mit MSC anderer Organe, deren therapeutisches Potenzial zur Behandlung von Lebererkrankungen gegenwärtig von vielen Arbeitsgruppen untersucht wird.

Schlüsselwörter

mesenchymale Stammzellen - MSC - Sternzellen - Ovalzellen - Leberstammzellen - Leberregeneration

Key words

mesenchymal stem cells - MSC - stellate cells - oval cells - liver stem cells - liver regeneration

• References

• 1 Michalopoulos GK, Khan Z. Liver Stem Cells: Experimental Findings and Implications for Human Liver Disease. Gastroenterology 2015; 149: 876-882
• 2 Furuyama K, Kawaguchi Y, Akiyama H et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 2011; 43: 34-41
• 3 Carpentier R, Suñer RE, van Hul N et al. Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology 2011; 141: 1432-1438
• 4 Sekiya S, Suzuki A. Hepatocytes, rather than cholangiocytes, can be the major source of primitive ductules in the chronically injured mouse liver. Am J Pathol 2014; 184: 1468-1478
• 5 Tarlow BD, Pelz C, Naugler WE et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 2014; 15: 605-618
• 6 Factor VM, Radaeva SA, Thorgeirsson SS. Origin and fate of oval cells in dipin-induced hepatocarcinogenesis in the mouse. Am J Pathol 1994; 145: 409-422
• 7 Schaub JR, Malato Y, Gormond C et al. Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury. Cell Rep 2014; 8: 933-939
• 8 Rodrigo-Torres D, Affò S, Coll M et al. The biliary epithelium gives rise to liver progenitor cells. Hepatology 2014; 60: 1367-1377
• 9 Jörs S, Jeliazkova P, Ringelhan M et al. Lineage fate of ductular reactions in liver injury and carcinogenesis. J Clin Invest 2015; 125: 2445-2457
• 10 Jelnes P, Santoni-Rugiu E, Rasmussen M et al. Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell-mediated liver regeneration. Hepatology 2007; 45: 1462-1470
• 11 Wang X, Foster M, Al-Dhalimy M et al. The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci USA 2003; 100 (Suppl. 01) 11881-11888
• 12 Huch M, Dorrell C, Boj SF et al. In vitro expansion of single Lgr5⁺ liver stem cells induced by Wnt-driven regeneration. Nature 2013; 494: 247-250
• 13 Petersen BE, Bowen WC, Patrene KD et al. Bone marrow as a potential source of hepatic oval cells. Science 1999; 284: 1168-1170
• 14 da Silva ML, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 2006; 119: 2204-2213
• 15 Crisan M, Yap S, Casteilla L et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 2008; 3: 301-313
• 16 Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008; 88: 125-172
• 17 Yin C, Evason KJ, Maher JJ et al. The basic helix-loop-helix transcription factor, heart and neural crest derivatives expressed transcript 2, marks hepatic stellate cells in zebrafish: analysis of stellate cell entry into the developing liver. Hepatology 2012; 56: 1958-1970
• 18 Kordes C, Sawitza I, Müller-Marbach A et al. CD133⁺ hepatic stellate cells are progenitor cells. Biochem Biophys Res Commun 2007; 352: 410-417
• 19 Genz B, Thomas M, Pützer BM et al. Adenoviral overexpression of Lhx2 attenuates cell viability but does not preserve the stem cell like phenotype of hepatic stellate cells. Exp Cell Res 2014; 328: 429-443
• 20 Covas DT, Panepucci RA, Fontes AM et al. Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146⁺ perivascular cells and fibroblasts. Exp Hematol 2008; 36: 642-654
• 21 Castilho-Fernandes A, de Almeida DC, Fontes AM et al. Human hepatic stellate cell line (LX-2) exhibits characteristics of bone marrow-derived mesenchymal stem cells. Exp Mol Pathol 2011; 91: 664-672
• 22 Kordes C, Sawitza I, Götze S et al. Hepatic stellate cells support hematopoiesis and are liver-resident mesenchymal stem cells. Cell Physiol Biochem 2013; 31: 290-304
• 23 Méndez-Ferrer S, Michurina TV, Ferraro F et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010; 466: 829-834
• 24 Dominici M, Le Blanc K, Mueller I et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315-317
• 25 Niki T, Pekny M, Hellemans K et al. Class VI intermediate filament protein nestin is induced during activation of rat hepatic stellate cells. Hepatology 1999; 29: 520-527
• 26 Meurer SK, Tihaa L, Lahme B et al. Identification of endoglin in rat hepatic stellate cells: new insights into transforming growth factor beta receptor signaling. J Biol Chem 2005; 280: 3078-3087
• 27 Andrade CM, Roesch GC, Wink MR et al. Activity and expression of ecto-5'-nucleotidase/CD73 are increased during phenotype conversion of a hepatic stellate cell line. Life Sci 2008; 82: 21-29
• 28 Kordes C, Sawitza I, Götze S et al. Stellate cells from rat pancreas are stem cells and can contribute to liver regeneration. PLoS One 2012; 7 e51878
• 29 Kordes C, Sawitza I, Götze S et al. Hepatic stellate cells contribute to progenitor cells and liver regeneration. J Clin Invest 2014; 124: 5503-5515
• 30 Baba S, Fujii H, Hirose T et al. Commitment of bone marrow cells to hepatic stellate cells in mouse. J Hepatol 2004; 40: 255-260
• 31 Miyata E, Masuya M, Yoshida S et al. Hematopoietic origin of hepatic stellate cells in the adult liver. Blood 2008; 111: 2427-2435
• 32 Friedenstein A, Kuralesova AI. Osteogenic precursor cells of bone marrow in radiation chimeras. Transplantation 1971; 12: 99-108
• 33 Loo CK, Pereira TN, Pozniak KN et al. The development of hepatic stellate cells in normal and abnormal human fetuses – an immunohistochemical study. Physiol Rep 2015; 3 e12504
• 34 Son BR, Marquez-Curtis LA, Kucia M et al. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells 2006; 24: 1254-1264
• 35 Sawitza I, Kordes C, Reister S et al. The niche of stellate cells within rat liver. Hepatology 2009; 50: 1617-1624
• 36 Correa D, Somoza RA, Lin P et al. Mesenchymal stem cells regulate melanoma cancer cells extravasation to bone and liver at their perivascular niche. Int J Cancer 2015; DOI: 10.1002/ijc.29709.
• 37 Kordes C, Häussinger D. Hepatic stem cell niches. J Clin Invest 2013; 123: 1874-1880
• 38 Barcellos-de-Souza P, Gori V, Bambi F et al. Tumor microenvironment: bone marrow-mesenchymal stem cells as key players. Biochim Biophys Acta 2013; 1836: 321-335
• 39 Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105: 1815-1822
• 40 Chen CH, Kuo LM, Chang Y et al. In vivo immune modulatory activity of hepatic stellate cells in mice. Hepatology 2006; 44: 1171-1181
• 41 Kaplan JM, Yound ME, Lodie TA. Immunomodulatory activity of mesenchymal stem cells. Curr Stem Cell Res Ther 2010; 6: 297-316
• 42 Schildberg FA, Wojtalla A, Siegmund SV et al. Murine hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism. Hepatology 2011; 54: 262-272
• 43 Zhang ZY, Zhou ZQ, Song KB et al. Hepatic stellate cells induce immunotolerance of islet allografts. Transplant Proc 2014; 46: 1594-1600
• 44 Dan YY, Riehle KJ, Lazaro C et al. Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. Proc Natl Acad Sci U S A 2006; 103: 9912-9917
• 45 Herrera MB, Bruno S, Buttiglieri S et al. Isolation and characterization of a stem cell population from adult human liver. Stem Cells 2006; 24: 2840-2850
• 46 Conigliaro A, Colletti M, Cicchini C et al. Isolation and characterization of a murine resident liver stem cell. Cell Death Differ 2008; 15: 123-133
• 47 Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem 2006; 98: 1076-1084
• 48 Yang L, Jung Y, Omenetti A et al. Fate-Mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers. Stem Cells 2008; 26: 2104-2113
• 49 Michelotti GA, Xie G, Swiderska M et al. Smoothened is a master regulator of adult liver repair. J Clin Invest 2013; 123: 2380-2394
• 50 Swiderska-Syn M, Syn WK, Xie G et al. Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. Gut 2014; 63: 1333-1344
• 51 Hu Z, Evarts RP, Fujio K et al. Expression of hepatocyte growth factor and c-met genes during hepatic differentiation and liver development in the rat. Am J Pathol 1993; 142: 1823-1830
• 52 Watanabe S, Hirose M, Wang XE et al. A novel hepatic stellate (Ito) cell-derived protein, epimorphin, plays a key role in the late stages of liver regeneration. Biochem Biophys Res Commun 1998; 250: 486-490
• 53 Kalinichenko VV, Bhattacharyya D, Zhou Y et al. Foxf1 +/- mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury. Hepatology 2003; 37: 107-117
• 54 Mabuchi A, Mullaney I, Sheard PW et al. Role of hepatic stellate cell/hepatocyte interaction and activation of hepatic stellate cells in the early phase of liver regeneration in the rat. J Hepatol 2004; 40: 910-916
• 55 Asai K, Tamakawa S, Yamamoto M et al. Activated hepatic stellate cells overexpress p75NTR after partial hepatectomy and undergo apoptosis on nerve growth factor stimulation. Liver Int 2006; 26: 595-603
• 56 Passino MA, Adams RA, Sikorski SL et al. Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75NTR. Science 2007; 315: 1853-1856
• 57 Van Hul NK, Abarca-Quinones J, Sempoux C et al. Relation between liver progenitor cell expansion and extracellular matrix deposition in a CDE-induced murine model of chronic liver injury. Hepatology 2009; 49: 1625-1635
• 58 Pintilie DG, Shupe TD, Oh SH et al. Hepatic stellate cells' involvement in progenitor-mediated liver regeneration. Lab Invest 2010; 90: 1199-1208
• 59 Shen K, Chang W, Gao X et al. Depletion of activated hepatic stellate cell correlates with severe liver damage and abnormal liver regeneration in acetaminophen-induced liver injury. Acta Biochim Biophys Sin 2011; 43: 307-315
• 60 Tsai SM, Wang WP. Expression and function of fibroblast growth factor (FGF) 7 during liver regeneration. Cell Physiol Biochem 2011; 27: 641-652
• 61 Zhu NL, Asahina K, Wang J et al. Hepatic stellate cell-derived delta-like homolog 1 (DLK1) protein in liver regeneration. J Biol Chem 2012; 287: 10355-10367
• 62 Chen L, Zhang W, Zhou QD et al. HSCs play a distinct role in different phases of oval cell-mediated liver regeneration. Cell Biochem Funct 2012; 30: 588-596
• 63 Nejak-Bowen KN, Orr AV, Bowen Jr WC et al. Gliotoxin-induced changes in rat liver regeneration after partial hepatectomy. Liver Int 2013; 33: 1044-1055
• 64 Mochizuki A, Pace A, Rockwell CE et al. Hepatic stellate cells orchestrate clearance of necrotic cells in a hypoxia-inducible factor-1α-dependent manner by modulating macrophage phenotype in mice. J Immunol 2014; 192: 3847-3857
• 65 Kocabayoglu P, Zhang DY, Kojima K et al. Induction and contribution of beta platelet-derived growth factor signalling by hepatic stellate cells to liver regeneration after partial hepatectomy in mice. Liver Int 2015; DOI: 10.1111/liv.12933.
• 66 Mogler C, Wieland M, König C et al. Hepatic stellate cell-expressed endosialin balances fibrogenesis and hepatocyte proliferation during liver damage. EMBO Mol Med 2015; 7: 332-338
• 67 Nagai H, Terada K, Watanabe G et al. Differentiation of liver epithelial (stem-like) cells into hepatocytes induced by coculture with hepatic stellate cells. Biochem Biophys Res Commun 2002; 293: 1420-1425
• 68 Uyama N, Shimahara Y, Kawada N et al. Regulation of cultured rat hepatocyte proliferation by stellate cells. J Hepatol 2002; 36: 590-599
• 69 Lin N, Tang Z, Deng M et al. Hedgehog-mediated paracrine interaction between hepatic stellate cells and marrow-derived mesenchymal stem cells. Biochem Biophys Res Commun 2008; 372: 260-265
• 70 Chan KM, Fu YH, Wu TJ et al. Hepatic stellate cells promote the differentiation of embryonic stem cell-derived definitive endodermal cells into hepatic progenitor cells. Hepatol Res 2013; 43: 648-657
• 71 Popp FC, Slowik P, Eggenhofer E et al. No contribution of multipotent mesenchymal stromal cells to liver regeneration in a rat model of prolonged hepatic injury. Stem Cells 2007; 25: 639-645
• 72 di Bonzo LV, Ferrero I, Cravanzola C et al. Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: engraftment and hepatocyte differentiation versus profibrogenic potential. Gut 2008; 57: 223-231
• 73 Mederacke I, Hsu CC, Troeger JS et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 2013; 4: 2823
• 74 Lua I, James D, Wang J et al. Mesodermal mesenchymal cells give rise to myofibroblasts, but not epithelial cells, in mouse liver injury. Hepatology 2014; 60: 311-322
• 75 Russo FP, Alison MR, Bigger BW et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology 2006; 130: 1807-1821
• 76 Mailloux AW, Zhang L, Moscinski L et al. Fibrosis and subsequent cytopenias are associated with basic fibroblast growth factor-deficient pluripotent mesenchymal stromal cells in large granular lymphocyte leukemia. J Immunol 2013; 191: 3578-3593
• 77 Judson RN, Zhang RH, Rossi FM. Tissue-resident mesenchymal stem/progenitor cells in skeletal muscle: collaborators or saboteurs?. FEBS J 2013; 280: 4100-4108
• 78 Christ B, Brückner S, Winkler S. The Therapeutic Promise of Mesenchymal Stem Cells for Liver Restoration. Trends Mol Med 2015; DOI: 10.1016/j.molmed.2015.09.004.
• 79 Trounson A, McDonald C. Stem Cell Therapies in Clinical Trials: Progress and Challenges. Cell Stem Cell 2015; 17: 11-22
• 80 Schwartz RE, Reyes M, Koodie L et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 2002; 109: 1291-1302
• 81 Jiang Y, Jahagirdar BN, Reinhardt RL et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418: 41-49
• 82 Kang XQ, Zang WJ, Bao LJ et al. Fibroblast growth factor-4 and hepatocyte growth factor induce differentiation of human umbilical cord blood-derived mesenchymal stem cells into hepatocytes. World J Gastroenterol 2005; 11: 7461-7465
• 83 Lange C, Bassler P, Lioznov MV et al. Liver-specific gene expression in mesenchymal stem cells is induced by liver cells. World J Gastroenterol 2005; 11: 4497-4504
• 84 Ong SY, Dai H, Leong KW. Hepatic differentiation potential of commercially available human mesenchymal stem cells. Tissue Eng 2006; 12: 3477-3485
• 85 Huang W, Ma K, Zhang J et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 2006; 312: 233-236
• 86 Sawitza I, Kordes C, Götze S et al. Bile acids induce hepatic differentiation of mesenchymal stem cells. Sci Rep 2015; 5: 13320
• 87 Kuwahara R, Kofman AV, Landis CS et al. The hepatic stem cell niche: identification by label-retaining cell assay. Hepatology 2008; 47: 1994-2002
• 88 Li TZ, Kim JH, Cho HH et al. Therapeutic potential of bone-marrow-derived mesenchymal stem cells differentiated with growth-factor-free coculture method in liver-injured rats. Tissue Eng Part A 2010; 16: 2649-2659