**4. Cell therapies**

Hepatocyte transplantation is certainly in the forefront of new therapeutic strategies. The first successful hepatocyte transplantation into a patient was carried out in June 1992 to a French Canadian woman with familial hypercholesterolaemia. After *ex vivo* transduction with a retrovirus encoding for the human LDL receptor, the patient's hepatocytes were infused through the inferior mesenteric vein into the liver. LDL and HDL levels improved throughout the next 18 months and transgene expression was detected in a liver biopsy(22). Following this first success, other patients followed through. However, not all the patients treated had a clear benefit from the procedure(23). Since then, several other metabolic diseases have been treated with hepatocyte transplantation with different degrees of success(24-28). It has also been used as a support treatment to acute(29-31) and chronic liver diseases(30-33) in bridging severely ill patients to orthotopic liver transplantation (OLT). Low efficacy and lack of long-term therapeutic effect have been common in all these procedures. These failures could be explained by the relatively small number of hepatocytes that engraft in the recipient liver due to quality, quantity and possibly immunosuppresion protocols(34). However, transplantation of a number of hepatocytes corresponding to 1-5% of the total liver mass has been able to show a positive impact in transplanted patients, even if for a limited period of time(34).

Due to the shortage of available human hepatocytes for transplantation, other cell sources have been used. Specifically, bone marrow derived mesenchymal stem cells(35), hematopoietic stem cells(36, 37) and fetal liver progenitor/stem cells(38) have shown to improve, to a certain extent, the condition of cirrhotic patients. The latter cell type holds an enormous potential for cell/regenerative medicine therapies due to their high expansion capabilities and differentiation into hepatocytes and biliary epithelium(39).

Recent data suggests that human embrionic (hES) and induced pluripotent (iPS) stem cells hold great promise to regenerative applications in every medical field. Specifically for the liver, several studies have established the required pathways to differentiate a hES or iPS into a hepatic fate by using defined soluble growth factor signals that mimic embryonic development(40, 41). These cells, once transplanted into rodent livers were able to engraft and express several normal hepatic functions(42). However, more extensive characterization, as well as further safety evaluation, are needed to determine wether these cells will fully function as primary adult hepatocytes.
