In the adult human liver, hepatic stem/progenitor cells (HPCs) are facultative bipotential stem cells which reside in the canals of Hering and in bile ductules. HPCs have a unique phenotype and are capable to differentiate towards hepatocytes and cholangiocytes. The differentiation toward a more mature phenotype is characterized by the progressive acquisition of mature traits and the appearance of a progeny with an intermediate phenotype.
HPCs are surrounded by a specialized niche, composed of portal myofibroblasts, hepatic stellate cells, and resident macrophages. The niche furnishes key signals, such as Notch and Wnt pathways, and drives HPC response, including proliferation and differentiation toward a mature fate.
In normal condition, HPCs are quiescent since the physiological turnover of liver parenchyma is endured by the proliferation of hepatocytes and cholangiocytes. The activation of HPC compartment takes place in human diseases when proliferative capabilities of mature cells are exhausted or impaired. The hallmark of HPC activation is represented by the appearance of the ductular reaction, which correlates with the severity of liver damage and is associated with fibrogenesis.
Beside HPCs, large intrahepatic and extrahepatic bile ducts contain a population of stem/progenitor cells collectively named biliary tree stem/progenitor cells (BTSCs). BTSCs reside within peribiliary glands along the biliary tree, are activated in human primary sclerosing cholangitis, and participate in biliary strictures.
The isolation of HPCs and BTSCs from adult or fetal human organs is easy, requires minimal manipulation and no reprogramming. The use of these cells has been proposed for the regenerative medicine of the liver and pancreas.
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Alvaro D, Gaudio E. Liver capsule: biliary tree stem cell subpopulations. Hepatology. 2016;64:644.CrossRefGoogle Scholar
Carpino G, Renzi A, Franchitto A, Cardinale V, Onori P, Reid L, Alvaro D, Gaudio E. Stem/progenitor cell niches involved in hepatic and biliary regeneration. Stem Cells Int. 2016;2016:3658013.CrossRefGoogle Scholar
Lanzoni G, Cardinale V, Carpino G. The hepatic, biliary, and pancreatic network of stem/progenitor cell niches in humans: a new reference frame for disease and regeneration. Hepatology. 2016;64:277–86.CrossRefGoogle Scholar
Spee B, Carpino G, Schotanus BA, Katoonizadeh A, Vander Borght S, Gaudio E, Roskams T. Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling. Gut. 2010;59:247–57.CrossRefGoogle Scholar
Gouw AS, Clouston AD, Theise ND. Ductular reactions in human liver: diversity at the interface. Hepatology. 2011;54:1853–63.CrossRefGoogle Scholar
Nakanuma Y, Sasaki M, Harada K. Autophagy and senescence in fibrosing cholangiopathies. J Hepatol. 2015;62:934–45.CrossRefGoogle Scholar
Williams MJ, Clouston AD, Forbes SJ. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion. Gastroenterology. 2014;146:349–56.CrossRefGoogle Scholar
Nobili V, Carpino G, Alisi A, Franchitto A, Alpini G, De Vito R, Onori P, Alvaro D, Gaudio E. Hepatic progenitor cells activation, fibrosis and adipokines production in pediatric nonalcoholic fatty liver disease. Hepatology. 2012;56:2142–53.CrossRefGoogle Scholar
Gadd VL, Skoien R, Powell EE, Fagan KJ, Winterford C, Horsfall L, Irvine K, Clouston AD. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology. 2014;59:1393–405.CrossRefGoogle Scholar
Nobili V, Alisi A, Cutrera R, Carpino G, De Stefanis C, D'Oria V, De Vito R, Cucchiara S, Gaudio E, Musso G. Altered gut-liver axis and hepatic adiponectin expression in OSAS: novel mediators of liver injury in paediatric non-alcoholic fatty liver. Thorax. 2015;70:769–81.CrossRefGoogle Scholar
Sancho-Bru P, Altamirano J, Rodrigo-Torres D, Coll M, Millan C, Jose Lozano J, Miquel R, Arroyo V, Caballeria J, Gines P, et al. Liver progenitor cell markers correlate with liver damage and predict short-term mortality in patients with alcoholic hepatitis. Hepatology. 2012;55:1931–41.CrossRefGoogle Scholar
Rastogi A, Maiwall R, Bihari C, Trehanpati N, Pamecha V, Sarin SK. Two-tier regenerative response in liver failure in humans. Virchows Arch. 2014;464:565–73.CrossRefGoogle Scholar
Carpino G, Cardinale V, Folseraas T, Overi D, Floreani A, Franchitto A, Onori P, Cazzagon N, Berloco PB, Karlsen TH, et al. Hepatic stem/progenitor cell activation differs between primary sclerosing and primary biliary cholangitis. Am J Pathol. 2018;188:627–39.CrossRefGoogle Scholar
Boulter L, Lu WY, Forbes SJ. Differentiation of progenitors in the liver: a matter of local choice. J Clin Invest. 2013;123:1867–73.CrossRefGoogle Scholar
Lorenzini S, Bird TG, Boulter L, Bellamy C, Samuel K, Aucott R, Clayton E, Andreone P, Bernardi M, Golding M, et al. Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver. Gut. 2010;59:645–54.CrossRefGoogle Scholar
Kallis YN, Robson AJ, Fallowfield JA, Thomas HC, Alison MR, Wright NA, Goldin RD, Iredale JP, Forbes SJ. Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response. Gut. 2011;60:525–33.CrossRefGoogle Scholar
Dubuquoy L, Louvet A, Lassailly G, Truant S, Boleslawski E, Artru F, Maggiotto F, Gantier E, Buob D, Leteurtre E, et al. Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis. Gut. 2015;64(12):1949–60.CrossRefGoogle Scholar
Grzelak CA, Martelotto LG, Sigglekow ND, Patkunanathan B, Ajami K, Calabro SR, Dwyer BJ, Tirnitz-Parker JE, Watkins DN, Warner FJ, et al. The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury. J Hepatol. 2014;60:143–51.CrossRefGoogle Scholar
Cardinale V, Wang Y, Carpino G, Cui CB, Gatto M, Rossi M, Bartolomeo Berloco P, Cantafora A, Wauthier E, Furth ME, et al. Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets. Hepatology. 2011;54:2159–72.CrossRefGoogle Scholar
Forbes SJ, Gupta S, Dhawan A. Cell therapy for liver disease: from liver transplantation to cell factory. J Hepatol. 2015;62:S157–69.CrossRefGoogle Scholar
Lanzoni G, Oikawa T, Wang Y, Cui CB, Carpino G, Cardinale V, Gerber D, Gabriel M, Dominguez-Bendala J, Furth ME, et al. Concise review: clinical programs of stem cell therapies for liver and pancreas. Stem Cells. 2013;31:2047–60.CrossRefGoogle Scholar
Rezvani M, Grimm AA, Willenbring H. Assessing the therapeutic potential of lab-made hepatocytes. Hepatology. 2016;64:287–94.CrossRefGoogle Scholar
Huch M, Gehart H, van Boxtel R, Hamer K, Blokzijl F, Verstegen MM, Ellis E, van Wenum M, Fuchs SA, de Ligt J, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell. 2015;160:299–312.CrossRefGoogle Scholar
Khan AA, Shaik MV, Parveen N, Rajendraprasad A, Aleem MA, Habeeb MA, Srinivas G, Raj TA, Tiwari SK, Kumaresan K, et al. Human fetal liver-derived stem cell transplantation as supportive modality in the management of end-stage decompensated liver cirrhosis. Cell Transplant. 2010;19:409–18.CrossRefGoogle Scholar
Cardinale V, Carpino G, Gentile R, Napoletano C, Rahimi H, Franchitto A, Semeraro R, Nuti M, Onori P, Berloco PB, et al. Transplantation of human fetal biliary tree stem/progenitor cells into two patients with advanced liver cirrhosis. BMC Gastroenterol. 2014;14:204.CrossRefGoogle Scholar