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Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration

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Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration cells Review Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration Antonietta Messina 1,2,3 , Eléanor Luce 1,2,3, Marwa Hussein 1,2,3 and Anne Dubart-Kupperschmitt 1,2,3,* 1 INSERM unité mixte de recherche (UMR_S) 1193, F-94800 Villejuif, France; [email protected] (A.M.); [email protected] (E.L.); [email protected] (M.H.) 2 UMR_S 1193, Université Paris-Sud/Paris-Saclay, F-94800 Villejuif, France 3 Département Hospitalo-Universitaire (DHU) Hépatinov, F-94800 Villejuif, France * Correspondence: [email protected]; Tel.: +33-145595138 Received: 30 November 2019; Accepted: 10 February 2020; Published: 12 February 2020 Abstract: The liver is a very complex organ that ensures numerous functions; it is thus susceptible to multiple types of damage and dysfunction. Since 1983, orthotopic liver transplantation (OLT) has been considered the only medical solution available to patients when most of their liver function is lost. Unfortunately, the number of patients waiting for OLT is worryingly increasing, and extracorporeal liver support devices are not yet able to counteract the problem. In this review, the current and expected methodologies in liver regeneration are briefly analyzed. In particular, human pluripotent stem cells (hPSCs) as a source of hepatic cells for liver therapy and regeneration are discussed. Principles of hPSC differentiation into hepatocytes are explored, along with the current limitations that have led to the development of 3D culture systems and organoid production. Expected applications of these organoids are discussed with particular attention paid to bio artificial liver (BAL) devices and liver bio-fabrication. Keywords: liver regeneration; human pluripotent stem cells; hepatocyte-like cells; cell transplantation; liver organoids; cell therapy; bio artificial liver devices; liver bio-fabrication; organ bioengineering 1. Introduction The liver is one of the most complex organs in the human body in terms of quantity and variety of functions. Defined as an exocrine and endocrine gland and as an organ, it is connected to the digestive system and performs numerous functions useful not only for the digestion of food but also for the defense of the body and the elimination of toxic substances. It is composed of different cell types including, at least, hepatocytes, biliary epithelial cells (cholangiocytes), stellate cells, Kupffer cells, and liver sinusoidal endothelial cells. Each of these cell types possesses unique functions, and their cooperation regulates hepatic function at multiple levels. The hepatocytes, in particular, represent 80% of the adult organ mass and perform almost all the functions related to its metabolic activity. Due to their high regeneration ability, these cells allow for the repair of damaged areas of the tissue, for example after restricted injury or surgery. However, the liver can indeed be damaged by viral infections and inherited genetic diseases, but also by an unbalanced life style, an excess of fat in the diet, unregulated alcohol consumption, smoking, drug use, and excess of medication, all inevitably leading to its dysfunction. Long-term damage can result in the loss of hepatocyte functions, which impacts liver regeneration ability. Liver damage may evolve as acute or chronic liver failure. Acute liver failure (ALF) occurs rapidly and can be due to any of the following: viral infections, such as hepatitis B (5%) or C Cells 2020, 9, 420; doi:10.3390/cells9020420 www.mdpi.com/journal/cells Cells 2020, 9, x FOR PEER REVIEW 2 of 22 Cells 2020, 9, 420 2 of 22 Acute liver failure (ALF) occurs rapidly and can be due to any of the following: viral infections, such as hepatitis B (5%) or C (12%); drug overdose or individual toxicity of medications (2.4%); metabolic (12%);disorders, drug such overdose as Wilson’s or individual disease toxicity (1%); of autoi medicationsmmune (2.4%);diseases metabolic (2%); and disorders, toxin exposure such as Wilson’s (4.4%). diseaseChronic (1%); liver autoimmune failure (CLF) diseasesis a life-threatening (2%); and toxin emergency exposure that (4.4%). passes Chronic through liver at least failure four (CLF) stages: is (i) a life-threateninginflammation; emergency(ii) fibrosis, that when passes healthy through tissue at least in inflamed four stages: liver (i) inflammation;is replaced by (ii) scar fibrosis, tissue; when (iii) healthycirrhosis, tissue in which in inflamed scars livercan isprevent replaced some by scar of the tissue; liver (iii) functions; cirrhosis, and in which (iv) end-stage scars can prevent liver disease some of(ESLD) the liver and/or functions; cancer. and CLF (iv) is end-stage generally liver the result disease of (ESLD) hepatitis and B/ oror cancer.C infection CLF (22%), is generally alcohol-related the result ofliver hepatitis diseases B or (19%), C infection nonalcoholic (22%), alcohol-related fatty liver di liversease, diseases genetic (19%), or autoimmune nonalcoholic fattyhepatitis liver (6%), disease, or geneticdiseases or that autoimmune affect the hepatitisbile duct (6%), system or diseases(14%). Antiviral that affect medications the bile duct and system immune (14%). suppressing Antiviral medicationsmedications andare available immune today suppressing to treat medications early stages areof liver available failure; today nonetheles to treats, earlycirrhosis stages is often of liver not failure;reversible nonetheless, and can be cirrhosis only slowed is often or not stopped. reversible Unfort andunately, can be onlywhen slowed ESLD oris reached, stopped. the Unfortunately, loss of liver whenfunctions ESLD is is too reached, important, the loss and of decompensation liver functions is in too other important, organs and and systems decompensation arises, including in other organshepatic andencephalopathy, systems arises, variceal including bleeding, hepatic kidney encephalopathy, impairment variceal, ascites, bleeding, and other kidney lung impairment,issues [1,2]. In ascites, these andcases, other the lungonly issuescurative [1, 2treatment]. In these is cases, liver transplantation the only curative [3]. treatment It is well-known is liver transplantation that the principal [3]. issue It is well-knownin liver transplantation that the principal is the issue shortage in liver of transplantation donors. In this is review, the shortage we present of donors. the Incurrent this review, available we presentmethodologies the current in liver available regeneration methodologies and the in new liver to regenerationols developed and during the new the tools last developeddecade (Figure during 1), thewith last the decade aim to (Figure discuss1 ),their with advantages the aim to and discuss weaknesses. their advantages In particular, and weaknesses.special attention In particular, is given to specialliver organoids, attention 3D is given structures to liver generally organoids, obtained 3D structures after differentiation generally obtained of human after pluripotent differentiation stem cells of human(hPSCs) pluripotent and able to stem reproduce cells (hPSCs) at least andone ableof the to native reproduce organ at functions. least one ofDespite the native the promising organ functions. results Despiteobtained the both promising in vitro resultsand in obtainedpre-clinical both trials,in vitro improvementsand in pre-clinical still need trials, to be improvements done on hPSC-derived still need tocells be doneand onorganoids. hPSC-derived However, cells andphysicians organoids. and However, researchers physicians are counting and researchers on these are new counting tools onfor theseimproving new tools organ for transplantation improving organ and transplantation for the developme and fornt theof new development therapies, of with new a therapies, special focus with on a specialpersonalized focus on medicine. personalized medicine. FigureFigure 1.1. SchematicSchematic timelinetimeline ofof liverliver therapytherapy andand regenerationregeneration approachesapproaches andand techniquestechniques [[4–17].4–17]. OLT:OLT: orthotopic orthotopic liver liver transplantation; transplantation; PHHs: PHHs:primary primary humanhuman hepatocytes;hepatocytes; AL:AL: artificialartificial liver;liver; iPSCs:iPSCs: inducedinduced pluripotent pluripotent stem stem cells; cells; LPC: LPC: liver liver progenitor progenitor cells; cells; BAL: BAL: bio bio artificial artificial liver. liver. 2. Liver Therapy and Regeneration Approaches: Pros and Cons 2. Liver Therapy and Regeneration Approaches: Pros and Cons 2.1. Orthotopic Liver Transplantation (OLT) 2.1. Orthotopic Liver Transplantation (OLT) Since 1983, orthotopic liver transplantation (OLT) has been considered the only medical solution availableSince to 1983, patients orthotopic with liver liver failure. transplantation Most transplants (OLT) involvehas been the considered whole organ; the however,only medical partial solution liver transplantationavailable to patients has been with performed liver failure. with Most increasing transplants frequency involve in recent the whole years, potentiallyorgan; however, allowing partial for theliver treatment transplantation of multiple has patients been performed from one donor.with incr Interestingly,easing frequency it has been in rece recordednt years, that potentially the age of transplantedallowing for patientsthe treatment has increased of multiple consistently patients infrom the one last donor. decade Interestingly, all over Europe it has as well been as recorded the age ofthat the
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