Sunday, July 3, 2011

Use of hepatocyte and stem cells for treatment of post-resectional liver failure: are we there yet?


Liver International

Volume 31, Issue 6, pages 773–784, July 2011
  1. Tarek M. Ezzat1,2,
  2. Dipok K. Dhar1,
  3. Philip N. Newsome3,
  4. Massimo Malagó1,
  5. Steven W. M. Olde Damink1,4
Article first published online: 18 APR 2011
DOI: 10.1111/j.1478-3231.2011.02530.x

Abstract

Post-operative liver failure following extensive resections for liver tumours is a rare but significant complication. The only effective treatment is liver transplantation (LT); however, there is a debate about its use given the high mortality compared with the outcomes of LT for chronic liver diseases. Cell therapy has emerged as a possible alternative to LT especially as endogenous hepatocyte proliferation is likely inhibited in the setting of prior chemo/radiotherapy. Both hepatocyte and stem cell transplantations have shown promising results in the experimental setting; however, there are few reports on their clinical application. This review identifies the potential stem cell sources in the body, and highlights the triggering factors that lead to their mobilization and integration in liver regeneration following major liver resections.
Abbreviations

ALF,
acute liver failure;
ASC,
adult stem cell;
BMSC,
bone marrow stem cells;
ECS,
embryonic stem cell;
HGF,
hepatocyte growth factor;
HSC,
haematopoietic stem cell;
HT,
hepatocyte transplantation;
IP,
ischaemic preconditioning;
iPS,
induced pluripotent stem cell;
LT,
liver transplantation;
MSC,
mesenchymal stem cell;
PLF,
postresectional liver failure;
PVE,
portal vein embolization;
SDF,
stem cell derived factor;
SOS,
sinusoidal obstruction syndrome.


Liver failure, which may either present in an acute or chronic form, is a growing health problem ranking as one of the leading causes of death worldwide. The aetiology and presentation of liver failure differs according to age. In children, the leading identifiable cause of acute liver failure (ALF) is acetaminophen-induced hepatic toxicity followed by metabolic and autoimmune liver disease (1). Although acetaminophen is the most common cause of ALF in adults in the UK, acute viral hepatitis is the leading cause worldwide (2).
In children, biliary atresia is the most common cause of chronic liver disease with excellent survival rates following liver transplantation (LT) (3). Cirrhosis, however, remains the most common cause of end stage liver disease in adults with its two main aetiologies; alcohol consumption and viral hepatitis C. The only established long-term successful treatment for these conditions is LT with long-waiting lists of patients to be transplanted (4). Patients with liver tumours are not treated with LT but with liver resections and have excellent post-operative recovery; however, liver failure may occur in about 2–5% of patients following liver resections with considerable mortality (5). LT maybe used in critical situations to rescue the liver following post-resectional liver failure (PLF) and has shown better survival rates than with any other method of treatment (6). There has been an ethical argument, however, as to the use of a liver graft for treatment of PLF. Also, patients with PLF have very high mortality rates when compared with the other indications of LT. For these reasons, PLF represents a complex and challenging problem to most liver surgeons. The current review will describe PLF and role of cell therapy in its prevention and treatment.

Post-resectional liver failure
Liver resection remains the gold standard of treatment for both primary and secondary liver tumours with the most common indications for liver resection being colorectal liver metastasis (7) followed by hepatocellular carcinoma and cholangiocarcinoma (8).
Advances in chemotherapeutic drugs and changes in the resectability criteria have improved survival in patients after resection of colorectal liver metastasis (9). The revolution in chemotherapy regimens with the introduction of 5-flurouracil, oxaliplatin and irinotecan has converted non-resectable liver metastases into resectable ones (10). This, however, is not without a toxic effect on the normal hepatic parenchyma where irinotecan has been shown to cause steatohepatitis (11). Oxaliplatin is highly effective but unfortunately, it often also produces severe liver damage with hepatic sinusoidal dilatation and extravasation of erythrocytes into the centrilobular hepatic zones, a condition known as sinusoidal obstruction syndrome (SOS). It is clinically characterized by increased bilirubin level, hepatomegaly, right upper quadrant pain and weight gain or development of ascites (12). The incidence of short-term post-operative complications on the other hand has increased with the more aggressive approaches and more specifically the occurrence of PLF (13). It has also been shown that development of SOS in rats following monocrotaline administration delays hepatocyte division leading to impaired liver regeneration and eventually PLF following hepatectomy (12). This data, however, has not been shown to occur in patients receiving oxaliplatin-based therapies. Although there was increased hepatocyte atrophy and necrosis in patients receiving oxaliplatin, there was no statistical significant difference in hepatocyte biological markers when compared with the control group (14).
Post-resectional liver failure is a dreadful complication following major hepatic resections occurring once the remnant liver volume falls below a critical threshold. It presents a spectrum that ranges from mild liver dysfunction to ALF. A similar problem occurs in patients following LT because of size mismatch between recipients and the graft resulting in a small for size syndrome (15). Several definitions for PLF exist; however, the best quantitative definition with specificity of 96.6% is the 50–50 criteria, which describes PLF as prothrombin time <50% and serum bilirubin >50% μmol on post-operative day 5. Serum bilirubin is preferred because prothrombin time may be altered by administration of fresh frozen plasma and a peak bilirubin of 7.0 mg/dl has been considered a specific cut-off value for PLF-related deaths (16, 17).
To prevent PLF, the acceptable remnant liver volume following a resection should be approximately 25% (18). However, this may change if the remaining liver is abnormal, where the required remnant volume of liver parenchyma would range from 30 to 40% in patients with chemotherapy-associated steatosis to 40–50% in case of cirrhosis. When the remnant liver volume falls below this critical threshold, liver failure develops.

Assessment and detection of post-resectional liver failure
Estimation of the function of the remaining liver volume is an essential pre-operative step in planning for a successful liver resection and is most commonly assessed by computed tomography (CT) scan. However, the function of the remaining liver may be compromised by cirrhosis or fibrosis, and therefore functional studies are needed. Indocyanine green is a substrate whose extraction depends on both the functioning hepatocyte mass and the hepatic blood flow. A safe resection would be considered when the indocyanine green retention is at least 14% at 15 min (19). Serum hyaluronate, which is eliminated by sinusoidal endothelial cells (SEC), also seems to be an interesting clinical marker for detection of the hepatic functional reserve (20). There are several scoring systems to predict PLF in patients with cirrhosis, most important is the Child–Pugh scoring system depending on the presence or absence of ascites, encephalopathy and measurement of albumin, bilirubin and prothrombin time (21).

Prevention
The main stay of management of PLF should focus on the prevention.

Pre-operative
Pre-operative correction of the patients' comorbidities is very important in prevention of PLF including special attention to the nutritional status. Parenteral nutrition provides adequate caloric intake and nitrogen support. Enteral nutrition on the other hand prevents gastrointestinal atrophy and preserves normal gut flora. No statistically significant differences could be detected between enteral and parenteral nutrition, however, patients with enteral nutrition show better post-operative immune competence (22). There have been debates regarding the routine performance of percutaneous transhepatic drainage in all patients with jaundice as it has shown no benefit in patients with obstructive jaundice resulting from tumours (23). More recently pre-operative biliary drainage was associated with a higher complication rate in head of pancreas tumours when compared with early surgery (24).
Pre-operative portal vein embolization (PVE) is an effective measure to induce hypertrophy of the contralateral lobe of the liver. The gain in the residual volume ranges between 4 and 21 ml/day and an average of 4–6 weeks is required before the operation (25). This procedure has led to an increase in the percentage of patients undergoing extended hepatectomies with fewer complications and a shorter hospital stay. This technique, however, is not always successful and may result in an increase in the size of the existing tumour (26).

Intra-operative and post-operative
Intra- and post-operative hypotension also plays a role in prolonging the hepatic ischaemia and this may result from either blood loss or sepsis; which has a suppressive effect on the kupffer cell function (27). Several measures have been described to reduce excessive intra-operative blood loss including total vascular occlusion or lowering the central venous pressure (28).
Patients who were subjected to ischaemic preconditioning (IP) through intermittent vascular occlusion were associated with less morbidity when compared with continuous vascular occlusion. There was no difference between both groups in term of mortality or development of liver failure (29). IP involves a short period of clamping (5–10) min followed by reperfusion (5–10) min followed by occlusion. This renders the liver more tolerant to subsequent prolonged episodes of ischaemia and has been shown to decrease the severity of liver necrosis through several mechanisms including the upregulation of cytokine TNF and IL-6 with downregulation of TGF-B (30).

Treatment
Owing to the low incidence of PLF, there is great difficulty in conducting a randomized controlled trial that would evaluate the effect of treatment in these patients (5). Patients with PLF should be treated in the ITU with invasive monitoring and support of the vital body functions. Owing to the strong association between sepsis and PLF, antibiotics should be administered empirically in the setting of PLF and later adjusted according to the results of the cultures taken (16). Several measures for liver support have been documented and could be divided into cell-free liver support systems and bioartificial livers. The former include plasma exchange (31) and the molecular absorbent recirculating system (32), none of which seem to provide definitive treatment for PLF as they cannot replace the synthetic and metabolic functions of the failing liver.
Bioartificial devices have been designed in the recent years to support functions of metabolic organs. They are basically extracorporeal bioreactors loaded with different cell types (33). The cells used in the liver model are either human or porcine hepatocytes (34). However, more research needs to be conducted focusing on developing an ideal bioreactor which should resemble both normal hepatic tissue structure and function (35). A more promising future management might be the application of stem cells or hepatocytes in the treatment of PLF.
The aim of the present review is to explore the possible role of cellular therapy in improving the remnant liver volume, henceforth, preventing and treating PLF using either pluripotent stem cells or isolated hepatocyte Transplantation (HT).

Cell therapy for treatment of post-resectional liver failure
Cell-based therapy is considered a new therapeutic tool that has shown great success in the recent years and is expected to replace whole-organ transplantation in the future. The target of cell therapy is to substitute the defective cells in order to substitute organ function through transplantation of cells (36). In case of larger tissue defects, cells alone cannot replace the function and tissue engineering is required to load cells on to 3-dimensional (3D) biodegradable scaffolding systems to support their growth and function (37). There are several sources of cells which can be used in prevention and treatment of PLF (Fig. 1).

Click Here For (Fig. 1).

Liver regeneration following partial hepatectomy
The ideal way of increasing the functioning residual liver volume following major hepatic resections would be through increasing the number of functioning hepatocytes. Replenishing the lost hepatocyte mass might occur through either stimulation of the endogenous hepatocytes or through an exogenous supply of hepatocytes or cells with the potential to differentiate into hepatocytes.
The liver has an enormous ability to regenerate, dependent primarily on the proliferation of hepatocytes. The hepatocytes are in a quiescent state in the intact liver and are non-responsive to growth factors. Following partial hepatectomy the hepatocytes are sensitized by TNF released from the non-parenchymal cells possibly because of an increase in the lipopolysccharide levels with a dramatic response of the hepatocytes to the released cascade of growth factors (38). Hepatocyte growth factor (HGF), epidermal growth factor receptor ligands and transforming growth factor-[alpha] are the primary mitogenic growth factors that initiate a powerful regenerative drive leading to rapid hepatic regeneration through proliferation of the hepatocytes. This occurs in coordination with proliferation of non-parenchymal cells and the support of the extracellular matrix (39).
Liver regeneration following partial hepatectomy requires two rounds of hepatocyte replication to restore the liver volume. The duration for complete restoration of the liver volume after a partial hepatectomy ranges from 5 to 7 days in rats and from 8 to 15 days in humans (40). Hepatocytes have been shown to have their highest DNA synthesis 24 h following the hepatectomy; followed by Kupffer cells at 48 h and endothelial cells at 96 h (41).
With more extensive liver resections, the regenerative drive of hepatocytes is insufficient (42) and regeneration then depends on the stimulation of a second compartment comprised of hepatic progenitor cells as described by Farber and colleagues (43, 44). They are bipotential cells with the ability to differentiate into either hepatocytes or biliary epithelial cells (45) (Figs 2 and 3). It is important to mention, however, that this only occurs when liver resection is associated with a background of chemical injury and not following liver resection per se (46). These oval cells reside in four possible 3D niches, most important of which are the canals of Hering representing the small peripheral branches of the biliary tree (47). The interaction between the cells in these niches with hormones and growth factors adds to their flexibility and regenerative capacity (48). These oval cells have been postulated to be the progenitors of hepatic stem cells because they share cell surface markers with haematopoietic stem cells (HSC) such as c-kit, Sca-1, Thy-1 and CD-34 (49). This may be clearly understood when looking at the common embryological origin, where hepatocytes, biliary epithelium and the pancreas originate from the foregut (50). Biliary epithelial cells appear capable of changing their phenotype and giving rise to hepatocyte-like cells, moreover gallbladder epithelial cells have been successfully engrafted in mouse recipient liver with similar morphological features and expression to hepatocytes (51). Whether this is because of the presence of bipotential stem cells or terminal transdifferentiation is yet to be investigated.

Click Here For (Figs 2 and 3).

Hepatocyte transplantation
The main sources of hepatocytes are livers that were judged inadequate for transplantation (52). Other sources include fetal hepatocytes which show higher proliferation and engraftment rates than adult hepatocytes (53). HT is most successful in treating congenital metabolic diseases of the liver in children and in adults (54). This may be explained by the low number of cells required to correct the underlying error, where replacement of 2–5% of the liver mass may improve the function dramatically (55). The quality of the transplanted cells is essential for efficient engraftment and is a major limiting factor for successful transplantation (56). Following injection there are three major steps that are required for liver repopulation which are deposition of hepatocytes into the hepatic sinusoids, traversing the SEC, which represent a physiological barrier to engraftment followed by integration into the liver parenchyma. Loss of cell viability in any of these steps would stimulate the phagocytic system to clear the non-viable cells (57).
The cells are most often delivered by an intraportal infusion directly into the liver; however, cells also survive and retain their function when injected into the spleen, which may be considered the best extra-hepatic organ for HT. Other sites include the thymus which has a good connective tissue network and adequate nutrient supply (58) and the peritoneal cavity for its large capacity and easy accessibility (59).
An important indication for HT is treatment of ALF which requires only temporary support until the liver regains its metabolic functions (60). The use of HT seems to be more effective with ALF than with chronic liver diseases because of the normal liver architecture and the better regenerative capacity of hepatocytes.
Hepatocyte-like cells known as NeoHeps that are derived from terminally differentiated peripheral blood monocytes also seem to be very effective in treating experimental ALF (61). There are very few clinical trials published, none of which provide evidence to show that patients who received HT for ALF showed better survival (62).
In addition to limited availability, problems in HT are that mature hepatocytes tend to de-differentiate in vitro and that multiple transplantation procedures are required to achieve a meaningful liver repopulation (63). This problem may be bypassed through transplantation of immortalized hepatocytes based on the use of a clonal cell line that could be grown in culture and exhibit the characteristics of differentiated non-transformed hepatocytes. Such cells could potentially provide an unlimited supply of well-characterized, pathogen-free liver cells (64). The malignant potential of these immortalized cell lines, however, needs to be fully investigated before they could be applied in the clinic. It is also thought that important interactions occur between hepatocytes and other cells in the body and this is difficult to replicate in standard culture conditions. Attempts at developing sophisticated culture systems may help solve this problem (65).
Currently, HT cannot present a reliable alternative to LT but might be able to bridge a period needed for regeneration or to stretch the waiting time for a suitable liver donation (66). Proper randomized clinical trials need to identify the approximate number of cells required for a successful transplant, and the rate of engraftment of these cells. Stem cells on the other hand present an interesting therapeutic promise owing to their pluripotency and unlimited supply.

Embryonic/induced pluripotent stem cell- derived hepatocytes
Embryonic stem cells (ESC) were first described more than two decades ago, when they were isolated from the inner cell mass of the developing murine blastocyst and grown in the laboratory (67). ESCs have since been shown to be pluripotent cells that can differentiate into cells from all lineages; also in vitro induction of human ESCs to differentiate into trophoblasts was possible under the influence of certain differentiation factors (68). The potential clinical application of ESCs is confronted, however, with many practical and ethical concerns (69). Equivalent to the ESCs in gene expression are the induced pluripotent stem cells (iPS), which have been generated from adult mouse fibroblast cells by retroviral transduction of four transcription factors (70). Furthermore, iPS cells have been generated from primary hepatocytes and gastric epithelial cells in mice (71). Recently iPS cells have also been derived from human skin (72). iPS cells involve a reversal of the developmental process removing most epigenetic marks laid down during development resulting in a pluripotent cell that must be differentiated into mature cells for therapeutic applications. A pancreatic exocrine cell may be converted to a β cell or an endocrine progenitor that produces all pancreatic endocrine cell types, or reprogramming a post-natal astroglia in the nervous system into a neuron or into a neural stem cell (73, 74). However, the application of iPS cells in the clinic may also be a question of debate towing to involvement of genetic manipulation that may lead to tumour formation in patients (75).

Adult bone marrow-derived hepatocytes
There are less ethical issues with using adult stem cells (ASC), which are undifferentiated cells, found throughout the body to replenish dying cells and regenerate damaged tissue. ASCs are stable cells and very rarely switch from one cell type to another, the occurrence of which may have serious consequences like metaplasia and cancer (76). There are several advantages in using ASCs in organ regeneration as they are immunocompatible as long as they are from autologous tissue, readily available and pose no ethical considerations.
The most readily available source of ASCs is the bone marrow which contains three stem cell subpopulations, which are the mesenchymal stem cells (MSC), HSCs and endothelial progenitor cells (77).

Mesenchymal stem cells
The role of bone marrow MSCs in liver regeneration has been heavily debated. MSCs are clonogenic, non-haematopoietic cells that are capable of differentiating into multiple mesoderm-type cell lineages (78). They constitute about 0.01–0.001% of bone marrow cells with the number being highest in neonates and decreasing with advancing age (79). When stimulated by specific signals, these cells can be released from their niche in the bone marrow into the circulation and recruited to the target tissues where they undergo in situ differentiation and integration and contribute to tissue regeneration and healing (80). Because of their extensive differentiation potential, MSCs were among the first stem cell types to be introduced in the clinic (81). It is unlikely that MSCs contribute directly towards generation of mature functioning hepatocytes, with their immunomodulatory or paracrine influence mediating their dominant effect on liver regeneration (82). MSCs are not immortal and there is a limit to the time in which they can be cultured in vitro, but this problem has been addressed by transducing them with the human telomerase reverse transcriptase gene in order to extend their life span and provide a large number of cells for therapeutic applications (83).
The therapeutic role of MSCs in liver regeneration must be further investigated as the clinical evidence is still limited, and MSCs may have a propensity to increase liver fibrosis in certain types of liver injury (84).

Haematopoietic stem cells
The role of bone marrow HSCs in liver regeneration will be covered in detail later in the section on prospects for stem cell transplantation in the treatment of hepatic disease. They have also been shown to replenish SEC; the integrity of which is a key factor in liver regeneration. SECs are damaged following administration of oxaliplatin as part of the neoadjuvant regimen before liver resection. The damage occurring is mainly through disruption of the SEC lining leading to portal hypertension and impairment of liver regeneration (12, 85, 86).
It has been shown that infusion of bone marrow derived CD 133+ cells in a rat model of SOS has successfully replaced significant portions of the SECs highlighting the beneficial role of bone marrow stem cells (BMSC) in treating SOS and hence accelerating liver regeneration (87).

Clinical applications of stem cells in regenerative medicine
Owing to the inability to harvest or expand stem cells from most adult organs especially heart, liver and brain, the majority of human stem cell trials have focused on clinical applications of MSCs, HSCs or both. In the past few years, extensive research has been carried out on treating spinal cord injuries using different types of stem cells. The main source of stem cells is the bone marrow where BMSC were transdifferentiated into neural tissue and transplanted into injured spinal cords of paraplegical animals resulting in functional improvement (88). There are some clinical trials that are running but sufficient data are still lacking.
Recent stem cell research points to the potential of cell therapy as a future treatment strategy for heart failure. Cell types used include multipotent progenitor cells, skeletal myoblasts, smooth muscle cells, fetal and embryonic cardiomyocytes, and both bone marrow stromal and HSCs. A recent clinical trial suggests that transplanted BMSCs injected into patients following acute myocardial infarction improved the cardiac function (89).
The introduction of islet cell transplantation in contrast to whole organ transplantation in treating diabetes mellitus has the benefit of being minimally invasive, however, the success rate of the approach is limited, and a very high per cent of the patients still require insulin after 1 year (90), and furthermore, advances are hampered by the shortage in cadaveric donor material. Stem cells derived from the bone marrow or reprogramming of the adult pancreatic cells into pancreatic progenitor cells which may be directed to secrete insulin may be possible through expression of certain transcriptional factors (91).

Stem cells and liver disease

Stem cells have been shown to improve liver function and survival in liver diseases and present an interesting alternative or adjunct to liver and HT.

Embryonic stem cells
Differentiating ESCs into cells with hepatocyte properties that are metabolically active and immunologically inert is a major goal in the field of tissue regeneration.
When ESCs were injected in their undifferentiated state into mice, they resulted in teratomas that killed the animals (92). However, ESC-derived hepatocytes were associated with improved survival when compared with undifferentiated ESCs in treating mice from ALF (93). From hence, came the need to develop an in vitro ESC differentiating system that would provide an unlimited source of functional hepatocytes without an increased risk of developing tumours.
There are several methods for inducing differentiation of undifferentiated ESCs. Embryoid bodies which resemble embryos in the early stages of development are formed when the culture conditions are changed to allow the ESCs to form 3D spherical structures (Figs 4 and 5), however, to induce differentiation, the leukaemia inhibitory factor, which is essential to maintain the undifferentiated state needs to be taken out of the culture medium (94). ESCs that were cultured for more than 12 days, were capable of expressing both albumin and urea without the need for any additional growth factors at any stage of maturation, in addition, when cells were cultured for more than 9 days, they were not associated with teratoma formation when transplanted through the portal vein of mice (95). Concerns remain about their differentiation to non-hepatic cells after infusion into immunocompromised mice raising concerns about their long-term safety (96). Other studies suggest that the addition of certain growth factors like fibroblast growth factor, HGF and oncostatin-M at different time points improve differentiation of ESCs into hepatocytes (97, 98), and when transplanted, they significantly suppressed the onset of fibrosis and improved the survival rate among the recipient mice (99). Transplantation of undifferentiated ESCs also proved to be useful in treating CCL4-induced fibrosis in mice without resulting in tumour formation (100). Developing coculture systems where ESCs are cultured with liver cells may present an alternative to adding exogenous growth factors. This has been established using hepatocytes (101), as hepatocytes secrete activin, which has been shown to induce endodermal differentiation (102). However, activin alone cannot induce hepatocyte differentiation and in a more recent study it was used in combination with sodium butyrate and HGF for complete maturation of ESCs into hepatocytes (103).

Click Here For (Figs 4 and 5),

Unfortunately, there have been no clinical trials using human ESCs to treat liver diseases in human patients because utilization of human ESCs is still under ethical debates.

Bone marrow stem cells
Intensive research is being conducted to evaluate the efficacy of using MSCs or HSCs as an alternative cell source to HT for treatment of liver disease. Ideally, BMSCs for transplantation would be derived from the patient himself as this would avoid the problem of immunorejection. It has been shown, however, that if bone marrow-derived MSCs were to be transplanted between different people, an exaggerated immunogenic response would not be elicited (104). This may be because of the lack of MHC molecules on MSCs (105); moreover, MSCs may exert an immunoregulatory effect through their inhibition of T-cell proliferation (106).

Experimental data
Several animal experiments have been conducted to understand the mechanism of action of BMSCs. Induced liver damage was an essential factor for cell recruitment and propagation in all experiments. In one study in an experimental murine model, infusion of MSCs following lethally induced ALF restored metabolic functions of the liver through differentiation into hepatocytes (107). The reduced cell requirement and the rapidity of rescue from ALF suggested a paracrine proliferative effect of MSCs on the endogenous hepatocytes rather than direct differentiation into hepatocytes which does not seem likely to occur. The paracrine effects of MSCs have also been studied in different organs where they exerted protective effect on the heart (108), and kidney (109). Also, systemic infusion of soluble factors secreted from MSCs provided a survival benefit and prevented the release of liver injury biomarkers (110). Another more recent study showed that transfer of the genetic material from MSCs to resident hepatocytes following 70% hepatectomy in rats improved hepatocyte proliferation and suppressed apoptosis both in vitro and in vivo (111).
Mesenchymal stem cells have also been used for improving liver regeneration in liver-transplanted rats with small for size syndrome. It has been proven that the addition of HGF promotes cell uptake in the recipient grafts with production of albumin, improved liver function and survival (112). Both HGF and stromal-derived factor-1 (SDF-1) have been shown to play an integral role in recruiting and homing of MSCs to damaged liver tissue (113). SDF-1 is a potent chemokine that binds to its CXC receptor 4 on HSCs. Expression of this receptor is higher in bone marrow HSCs when compared with peripheral blood HSCs and elevation of the plasma levels of SDF-1 was found to be responsible for mobilization of stem cells from the bone marrow to peripheral blood down an SDF-1 gradient (114). In another study both resident hepatic stem cells and CD90+ BMSC have been indentified in liver sections of rats where a small for size LT was conducted in attempt to understand its effect on mobilizing stem cell populations (115). This also proves that both the liver and the HSCs contribute to liver regeneration.
Another theory is the mobilization of endothelial progenitors, which may be because of the increased serum level of vascular endothelial growth factor following the vascular damage associated with LT. In animals, it has been shown that circulating CD133+ and CD34+ cells are known to contribute to neo-angiogenesis after tissue ischaemia and organ regeneration in animal models (116).
There is definitely a correlation between the type of injury and the mobilization of different cell populations to rescue the liver. Whereas IP liver damage associated with LT induced the extensive mobilization of several subsets of haematopoietic and endothelial BMSC, liver resection regardless of extent was a weaker stimulus to recruit significant numbers of bone marrow cells despite the increase of the serum level of haematopoietic cytokine (117).

Clinical data
The stimuli for stem cell mobilization from the bone marrow and the resulting population of progenitor cells seem to be an important key in designing future therapies. Granulocyte colony stimulating factor (GCS-F) and certain chemotherapy protocols have resulted in a significant mobilization of progenitor cells that were used for bone marrow transplantation (118). The same principles have been applied in trials to treat patients with chronic liver diseases. In one study, CD34+ cells were derived from the peripheral blood of nine patients with alcoholic cirrhosis. These cells were expanded in vitro and injected into the hepatic arteries of the patients resulting in significant improvement of the Child–Pugh score (119). This might not be possible, however, in liver resections for malignant tumours as GCS-F might enhance tumour growth and increase the risk of splenic rupture which might add to the mortality of PLF patients (120).
It is of interest that liver donors showed a great increase of the circulating CD133+ cell population 12 h after a partial hepatectomy when compared with 1 day before the procedure. The origin of these cells is not known, but might be the liver itself because no increase was noted in other surgical procedures (121).
There have been only two clinical studies which were performed to assess the use of HSCs for PLF prevention.
These studies were conducted on a small number of patients who were expected to undergo major hepatic resections for cancer. The infusion of the CD133+ cells was combined with PVE which was important to induce a strong proliferative stimulus and to promote the uptake and engraftment of the cells. CD133+ cells were derived from the bone marrow and highly enriched in vitro then injected into the left lobe of the liver through the portal branches with subsequent PVE of the right liver segments to expand the left hepatic segments. CT volumetric scans showed an increase in the proliferation rate of the left lobe when compared with the control group (122, 123). The main advantage of combining CD133+ cells with PVE would be to reduce the waiting time between PVE and the operation in patients with rapidly progressing tumours and to increase the liver reserve in patients with small left lateral liver segments.

Conclusion
Surgeons are often confronted with a big challenge to perform partial hepatectomy for intended curative resections in patients with advanced tumours or with advanced cirrhosis. None of the current therapies has proved to be effective in treating PLF and LT which might be curative remains to be a debatable option because of the high mortality associated with the condition. Prevention of the condition from occurrence should therefore be the best approach and this may be through expanding the remnant liver volume following liver resection using cell therapy. Currently, HT is being effectively used to treat in-born errors of metabolism especially in children, however, in order to replace LT; greater numbers of differentiated cells from other sources with hepatocyte functions need to be used. The timing and degree of optimum differentiation of these cells and the capacity of the in vivo inductive microenvironment to complete the differentiation process without tumour formation needs to be further investigated.

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