the liver has a remarkable capacity to regenerate in response to injury ; however , in severe cases its regenerative capacity may prove to be insufficient , and the liver injury may progress to end - stage liver disease ( esld ) and subsequent liver failure . up to two million people suffer from chronic liver disease in the uk , many of whom remain unaware of their illness [ 1 , 2 ] . chronic liver disease is the fifth leading cause of death in the uk after cancer , cardiovascular disease , stroke , and respiratory disease . alcoholic liver disease ( ald ) , one of the major medical complications of alcohol abuse , is the commonest cause of esld in europe and north america and is one of the most controversial indications for transplantation . alcohol abuse accounts for 80% of all liver cirrhosis cases seen in district general hospitals in the united kingdom   and for a substantial and increasing proportion of all liver transplants performed . chronic liver disease ( cld ) due to alcohol abuse continues to rise . in 2005 , 4,160 people died in england and wales from alcoholic liver disease , an increase of 37% since 1999 . alcoholic liver cirrhosis ( alc ) has an unfavourable prognosis , with a mortality of 49% and 90% after 1 and 15  yr of followup , respectively .   at present orthotopic liver transplantation is the only therapeutic option for patients with acute and chronic eslds . liver transplantation , however , has the disadvantage of requiring lifelong immunosuppression and followup , with 1015% of patients dying whilst on the waiting list due to the shortage of donated organs . in 2005 , only one - third of patients waiting for a liver transplant were transplanted . with the number of donor organs likely to decrease over the coming decades , research into the alternative methods of treatment of whole - organ transplant is essential . hepatocyte transplantation has been suggested as an alternative to liver transplantation , especially for hepatic disorders caused by inherited protein deficiency . the widespread application of hepatocyte transplantation , however , is also limited by organ availability , by problems with viability of isolated hepatocytes after cryopreservation , and by the potential formation of hepatocyte aggregates during injection subsequently obstructing liver sinusoids and resulting in portal hypertension or fatal emboli . recent advances in the understanding of stem cell biology and plasticity have raised expectations for using stem cells as a new type of cellular therapy in regenerative medicine . in particular , adult hematopoietic stem - cell ( hsc- ) based treatment is evolving as a viable clinical alternative . these cells are capable of differentiating into many types of tissues , including skeletal and cardiac muscles , neuronal cells , pneumocytes , and hepatocytes . although stem cell therapy is not classically considered within the realm of clinical medicine , this technology will become increasingly important for clinicians in the future . the bm compartment is largely made up of hscs , committed progenitor cells , and noncirculating stromal cells called mesenchymal stem cells ( msc ) which have the ability to develop into mesenchymal lineages [ 9 , 10 ] . haematopoietic stem cells are adult stem cells that can be identified by their ability to differentiate into all blood cell types and reconstitute the haematopoietic system in a host that has been lethally myeloablated . it was previously thought that adult stem cells were lineage restricted , but recent studies have shown that bm - derived progenitors participate in the regeneration of ischaemic myocardium , damaged skeletal muscle , and neurogenesis , in addition to haematopoiesis . this paper focuses on the potential of hscs in the management of cld , concentrating on experimental models in animal and human tissue along with the current status of clinical trials . one of the first demonstrations of the ability of bmscs to reconstitute liver was reported by petersen and colleagues in 1999 . lethally irradiated female rats with induced hepatic injury , treated with 2-aminoacetylfluorine to prevent hepatic proliferation , and were rescued using bone marrow transplants from syngeneic males . the y - chromosome markers dipeptidyl peptidase iv enzyme ( dppiv ) and l21 - 6 antigen were used to identify liver cells of bm origin . this cross - sex model allowed the identification of male liver cells in the female rats ' livers indicating that bm - derived hscs have the capacity to transdifferentiate into hepatocytes . although evidence of transdifferentiation to hepatocytes is compelling from animal studies , few have examined this possibility in humans . alison and associates detected y - chromosome - positive cells in a retrospective analysis of the livers of 9 female recipients of bone marrow transplants from male donors . the authors also looked for the presence of y - chromosome - positive cells in 11 female livers transplanted to male recipients that were later removed due to recurrent disease , finding a number that expressed cytokeratin-8 ( 0.5%2% ) . there is much controversy concerning the mechanism by which bmscs contribute to hepatocyte regeneration or to liver repair . transdifferentiation into hepatocytes represents genomic plasticity in response to the microenvironment and has been shown in several experiments in vivo [ 1719 ] . however , some authors have proposed that conversion to hepatocytes may occur via cell fusion [ 20 , 21 ] . the so - called  bystander effect is postulated to be due to factors secreted by bmscs that are chemoattracted to the site of injury , leading to the stimulation of mitosis of endogenous liver cells . this mechanism is thought to recruit endogenous bm for cardiac repair following myocardial infarction following administration of granulocyte colony - stimulating factor ( g - csf ) . other possible explanations for target organ regeneration and improvement in function include facilitating the release of vascular endothelial growth factor ( vegf ) by stem cells , thus , increasing the blood supply to cells and helping to repair damaged tissue . stem cells may also act by up - regulating the bcl-2 gene and suppressing apoptosis   or by suppressing inflammation in the diseased organ via the interleukin-6 ( il-6 ) pathway . both of these processes are thought to contribute to the regeneration of normal cells in the damaged organ . finally , hscs may stimulate tissue - specific stem cells , such as oval cells in the liver , facilitating regeneration of the target organ . jang and colleagues transplanted enriched cd45 hscs into lethally irradiated mice treated with a single dose of carbon tetrachloride ( ccl4 ) . in this model , 7.6% of liver cells were of donor origin within 7 days of transplantation . there was early amelioration of liver disease with some improvement in liver function in transplanted mice compared to controls . the most promising study to date demonstrates liver disease reversal following transplantation of enriched hscs into fumarylacetoacetate hydrolase- ( fah- ) deficient mice , an animal model of tyrosinemia type i . bone marrow from metabolically competent donor mice was transplanted into a lethally irradiated fah - deficient mouse strain , resulting in the proliferation of large numbers of donor lacz hepatocytes and restoration of liver biochemical function . however , an animal study to investigate whether transplantation of hscs cd34 could improve hepatic fibrosis by their differentiation into hepatocytes found differing results . hscs from human umbilical cord blood were purified , transduced with a lentiviral vector containing the green fluorescent protein ( gfp ) gene , and injected via the portal vein into rats with liver cirrhosis induced by the four - month administration of thioacetamide . rats were killed at 15 and 60 days following transplantation . up to 37% and 22% fluorescent cells were observed in the blood of control and cirrhotic rats respectively , at 15 days after transplantation . at 60 days after transplantation ; however , fluorescent cells were completely absent from the blood . fluorescence was not detected in liver sections at either 15 or 60 days after transplantation . a polymerase chain reaction study to detect the gfp gene ruled out silencing of the transgene . these results suggest that the transplanted cells did not engraft in the liver and were eliminated from the rats . oyagi and associates have transplanted mscs , induced to adopt hepatocyte phenotype in vitro , intravenously into nonirradiated ccl4-damaged recipients and observed both a rise in serum albumin and a histological decrease in hepatic fibrosis . similarly , jiang et al . transplanted rosa26 mouse multipotent adult progenitor cells ( mapc ) into nonobese diabetic / severe combined immunodeficiency disease ( nod / scid ) mice sacrificing them 424 weeks later . since there was no noxious liver injury creating a donor cell survival advantage , there was no increase in the number of donor cells in the 6-month after transplant period . persistent injury has been found to induce efficient trans - differentiation of bmcs into functional hepatocytes . green fluorescent protein- ( gfp- ) transfected bmcs from nontreated mice injected into those with liver cirrhosis induced by ccl4 efficiently migrated into the periportal area of liver lobules after one day , repopulating 25% of the recipient liver by 4 weeks . in contrast , no gfp - positive bmcs were detected following transplantation into control mice with undamaged livers . serum albumin levels were significantly elevated to compensate for chronic liver failure in bmc transplantation suggesting that recipient conditions and microenvironments are key factors for successful cell therapy using bmcs . several studies have demonstrated the presence of cells of bone marrow origin in the human liver . alison and colleagues   elegantly demonstrated that adult human liver cells can be derived from stem cells originating in bone marrow . analysing livers from female patients who had received a bone marrow transplantation from a male donor , they found y - chromosome- and ck8- positive hepatocytes , thus , suggesting that extrahepatic stem cells can engraft in the liver . theise et al .   also studied autopsy and liver biopsy tissue from recipients of sex - mismatched therapeutic bone marrow and orthotopic liver transplantations . they identified hepatocytes and cholangiocytes of bone marrow origin by immunocytochemistry staining for ck8 , ck18 , and ck19 and fish analysis for the y - chromosome . they found up to 43% of hepatocytes and 38% of cholangiocytes were engrafted , showing that these cells can be derived and differentiated from bone marrow to replenish the liver . korbling and associates , for example , confirmed bone marrow - derived hepatocytes in liver biopsies of sex - mismatched bone marrow transplantation , but these represented only 4%7% of hepatocytes . similarly , ng et al .   showed that only a small proportion of hepatocytes ( 1.6% ) were recipient derived in the liver allografts . the inconsistency of these studies may relate to the use of varying techniques and markers to identify recipient - derived hepatocytes in the transplanted patients . although studies have shown that bone marrow stem cells can give rise to hepatocytes , the use of bone marrow stem cells as therapeutic agents is still in its infancy . these studies generally involve the mobilisation of bone marrow stem cells using granulocyte colony - stimulating factor ( g - csf ) or infusion of collected bone marrow stem cells , either peripherally or directly into the hepatic vasculature ( table 1 ) . our group conducted a phase i clinical trial of the infusion of cd34 cells into the portal vein or the hepatic artery of five patients with chronic liver disease with no adverse effects . although these patients received relatively low numbers of cells ( 2  10 ) , a moderate improvement in serum bilirubin was seen in 3 of the 5 patients which lasted for more than 18 months . our experience is in keeping with the observations made by am esch ii and associates , who in their first publication demonstrated increased liver regeneration in 3 patients following intra - portal administration of autologous cd133 bm cells into the left lateral portal vein branches during right portal vein embolisation ( pve ) . by ct criteria , left lateral segment hypertrophy was 2.5-fold higher compared to 3 patients that had right pve only . in their second publication , which included patients from the first study , they recruited a total of 13 patients . there was a significant increase in the daily liver growth in patients who had stem cell infusions in addition to pve ( n = 6 ) when compared to patients with pve alone ( n = 7 ) . terai and colleagues have also shown improvement in liver function following peripheral infusion of autologous bm cells in patients with liver cirrhosis . nine patients who received a peripheral vein infusion of an average of 5.2  10 autologous mononuclear cells ( cd34 , cd45 , and ckit ) demonstrated significant improvement in the child - pugh scores and serum levels of albumin . liver biopsies were taken in 3 patients revealing an increase in proliferating cell nuclear antigen staining , an indirect marker of hepatocyte turnover . yannaki and associates have reported 2 patients with alcohol - induced liver cirrhosis treated with autologous mobilised hscs . each patient underwent three rounds of g - csf mobilisation and peripheral vein infusion of cd34 cells . the procedure was well tolerated , and both patients improved their baseline child - turcotte - pugh ( ctp ) and model for end - stage liver disease ( meld ) scores during 30 months of followup . a further 2 patients with hepatitis - b - related decompensated liver cirrhosis treated with mobilised autologous peripheral blood monocytes ( pbmc ) also showed an improvement in serum albumin , bilirubin , alanine aminotransferase ( alt ) , aspartate aminotransferase ( ast ) , and ctp scores for greater than one year following transfusion . lyra and associates performed a study on 10 patients with chronic end - stage liver disease , receiving committed progenitor cells and no bm cells via the hepatic artery . this study showed improvement in serum bilirubin , albumin , and international normalised ratio ( inr ) . they went on to perform the first randomised controlled study of autologous bmc transplantation in liver disease . thirty patients were randomised to receive either a placebo or bmc , in the form of an autologous mononuclear cell preparation infused into the hepatic artery . after 3 months followup , the treated patients had a significant improvement in albumin compared to controls ( 16% versus 2% ) and a significant reduction in their child - pugh status ( 8% versus + 4% ) . have also reported the successful use of autologous cd34 bmscs via the portal vein as a rescue treatment in a patient with drug - induced acute liver failure .   a liver biopsy performed at 20 days following infusion showed increased hepatocyte replication around necrotic foci the patient , however , died secondary to multiorgan failure related to bacterial infection . in a study by khan and colleagues , four patients with liver insufficiency all patients showed improvements in serum albumin , bilirubin , and alt after one month from the cell infusion . in contrast to the previous studies , a trial of 4 patients with decompensated cirrhosis treated with cd34 stem cells via the hepatic artery was stopped prematurely due to one patient developing nephropathy and hepatorenal syndrome secondary to radiocontrast . the same group showed that msc transplantation in a further 4 patients with decompensated liver cirrhosis , this time via a peripheral vein , was well tolerated and resulted in a meld score improvement in two . another study injecting msc into either peripheral veins or the portal vein of patients with esld having a meld score 10 ( n = 8) showed significant improvement in their meld score . kim et al . reported significant improvement in serum albumin , quality of life , and the child - pugh score in ten patients with advanced liver cirrhosis due to hepatitis b infection following autologous bone marrow infusion . finally , our group has published the results of administering autologous expanded mobilised adult bm cd34 cells via the hepatic artery in 9 patients with alcoholic liver cirrhosis . significant decreases in serum bilirubin , alt , and ast levels were observed , whilst the child - pugh scores and radiological ascites improved in 7 and 5 patients , respectively . although all clinical trials to date have shown some improvement in liver function , it must be remembered that the natural history of cirrhosis tends to be variable . thus , one would expect some patients to improve with time , particularly in compliant patients who can be followed up and remain abstinent from alcohol . the liver contains approximately 2.8  10 hepatocytes , and the required mass of cells to correct a single enzyme biochemical defect is likely to be significantly less than that required for treatment of chronic or acute liver failure . there is evidence to suggest that transplantation of only 15% of the total liver mass may be sufficient to restore adequate functional activity [ 7 , 50 ] . cells can be delivered to patients via a peripheral vein , the portal vein , hepatic artery , or an intrasplenic injection . as both fulminant and chronic , liver failure requires the replacement of greater than 10% of functional liver ; the cell mass required for transplantation will be significantly higher . stimulation of regeneration , such as a partial hepatectomy , promotes increases in carbamoyl phosphate synthetase i activity with subsequent liver hypertrophy . this early experience suggests that this therapeutic approach has the potential of both enhancing and accelerating hepatic regeneration in a clinical setting .   unlike hepatocytes , the use of bmscs for liver regeneration does not depend on the procurement of cadaveric livers whose donors are often immunologically disparate and also in short supply . the use of adult stem cells is attractive as it overcomes the moral and ethical barriers of es cell manipulation . further advantages of the use of bmscs are that they are multipotent , there is already considerable experience in their use , they are easily accessible , and there is unlimited supply . conversely , concerns have been raised about the adverse long - term effects of stem cell therapy . there is evidence to suggest that treatment with bmscs may provide liver fibrogenic cells ( hepatic stellate cells and myofibroblasts ) which contribute to fibrosis and could have a deleterious effect on already decompensated cirrhotic livers [ 52 , 53 ] . similarly , there are concerns that hepatocellular carcinoma ( hcc ) originates from hepatic oval cells and bmscs . much of the data concerning the malignant potential of bmscs , however , originates from genetically modified rodent models and may not be present in humans . new findings in adult stem cell biology are transforming our understanding of tissue repair raising hopes of successful regenerative hepatology . although all clinical trials to date have shown some improvement in liver function and cd34 cells have been used safely for bm transplantation for over 20 years , only randomised controlled clinical trials will be able to fully assess the potential clinical benefit of adult stem cell therapy for patients with liver insufficiency secondary to ald .