Hepatic regenerative medicine
Authors: Giuseppe Mazza, Paolo De Coppi, Paul Gissen, Massimo Pinzani
Journal: Journal of Hepatology (2015)

The first human liver transplantation was performed by Thomas Starzl in 1963. Orthotopic liver transplantation (OLT) has evolved dramatically over the past 50 years and it is now established as a definitive treatment of most types of liver failure [[1]Zarrinpar A. Busuttil R.W. Liver transplantation: past, present and future.Nat Rev Gastroenterol Hepatol. 2013; 10: 434-440Crossref PubMed Scopus (164) Google Scholar]. However, whole organ transplantation is mostly limited by the unavailability of a sufficient number of suitable donor organs. Therefore, other approaches such as hepatocyte transplantation and tissue engineering represent an area of intense investigation. Transplantation of hepatocytes into the liver or spleen has expanded dramatically over the last decade, especially for the treatment of patients with liver-based inborn errors of metabolism [[2]Fox I.J. Chowdhury J.R. Kaufman S.S. Goertzen T.C. Chowdhury N.R. Warkentin P.I. et al.Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation.N Engl J Med. 1998; 338: 1422-1426Crossref PubMed Scopus (950) Google Scholar]. While this procedure appears safe in humans, its applicability remains limited by major technical issues and particularly a poor initial and long-term hepatocyte engraftment. Liver tissue engineering has been explored using both synthetic and biologic scaffolds. Perfusion decellularisation retains the architecture of the original organ, including the vascular tree and any specialized structures. Whole decellularised liver scaffolds repopulated with hepatocytes were used to generate transplantable recellularized liver graft. Long term transplantation of engineered rat livers using decellularised matrices have demonstrated to be efficient in 90% hepatectomy models [[3]Bao J. Shi Y. Sun H. Yin X. Yang R. Li L. et al.Construction of a portal implantable functional tissue-engineered liver using perfusion-decellularized matrix and hepatocytes in rats.Cell Transplant. 2011; 20: 753-766Crossref PubMed Scopus (113) Google Scholar] and have been attempted using large animal models [[4]Barakat S. Abbasi S. Rodriguez G. Rios J. Wood P. Ozaki C. et al.Use of decellularized porcine liver for engineering humanized liver organ.J Surg Res. 2012; 173: e11-e25Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar]. In 1992, Starzl and Colleagues transplanted baboon livers into patients with HIV infection and advanced hepatitis B, who survived 27 and 70 days, respectively. However, massive immunosuppression was necessary thus leading to fatal infections in both patients [[5]Starzl T.E. Iwatsuki S. Van Thiel D.H. Gartner J.C. Zitelli B.J. Malatack J.J. et al.Baboon-to-human liver transplantation.Lancet. 1993; 341: 65-71Abstract PubMed Scopus (371) Google Scholar]. Indeed the immunological barrier, mediated by xenoreactive natural antibodies (XNA) against a surface antigen (α-Gal) on porcine endothelial cells [[6]Kuwaki K. Tseng Y.L. Dor F.J. Shimizu A. Houser S.L. Sanderson T.M. et al.Heart transplantation in baboons using alpha1,3-galactosyltransferase gene-knockout pigs as donors: initial experience.Nat Med. 2005; 11: 29-31Crossref PubMed Scopus (603) Google Scholar], represents the major limitation for xenotrasplantation. Bioartificial liver support systems aim to temporarily replace the metabolic and excretory functions of the liver until the patients' own liver has recovered or a donor liver becomes available for transplant. The main components of BAL are extracorporeal bioreactors in which liver cells are cultured in a network of hollow fibres for blood plasma perfusion. Several clinical trials have been performed using this technology in patients with acute or acute-on-chronic liver failure. A recent meta-analysis has shown an improvement in survival in patients with acute liver failure while there was no evidence that this system improved survival in acute-on-chronic liver failure [[7]Stutchfield B.M. Simpson K. Wigmore S.J. Systematic review and meta-analysis of survival following extracorporeal liver support.Br J Surg. 2011; 98: 623-631Crossref PubMed Scopus (96) Google Scholar]. Combination of gene and cell therapy was first attempted by James Wilson in a patient with homozygous familial hyperlipidaemia [[8]Grossman M. Raper S.E. Kozarsky K. Stein E.A. Engelhardt J.F. Muller D. et al.Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia.Nat Genet. 1994; 6: 335-341Crossref PubMed Scopus (516) Google Scholar]. A segment of the patient's liver was resected and autologous hepatocytes were then infected ex vivo with the retrovirus containing LDL receptor gene. The encouraging early biochemical correction, however, was not sustained. Patient derived induced pluripotent stem cells (iPSc) in combination with novel genome editing technologies were used by Ludovic Vallier to correct mutations in SERPINA1 in iPSc derived from patients with alpha1-anti-trypsin deficiency using zinc finger nucleases and piggyBac transposon. The corrected iPSc were then differentiated into hepatocytes and successfully tested in vivo in a mouse model thus providing the first proof of principle study for an individualised liver cell therapy using iPSc [[9]Yusa K. Rashid S.T. Strick-Marchand H. Varela I. Liu P.Q. Paschon D.E. et al.Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells.Nature. 2011; 478: 391-394Crossref PubMed Scopus (562) Google Scholar]. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.