New insights into liver stem cells
Article Outline
- Abstract
- 1. Introduction
- 2. Hepatic progenitor cells
- 3. Activation of HPCs
- 4. Hepatic progenitor cells in human liver pathologies
- 5. Hepatic progenitor cells niche and its role in HPCs activation
- 6. Isolation of HPCs and their possible use in end-stage chronic liver diseases
- 7. Concluding remarks
- Conflict of interest statement
- References
- Copyright
Abstract
Hepatic progenitor cells are bi-potential stem cells residing in human and animal livers that are able to differentiate towards the hepatocytic and the cholangiocytic lineages. In adult livers, hepatic progenitor cells are quiescent stem cells with a low proliferating rate, representing a reserve compartment that is activated only when the mature epithelial cells of the liver are continuously damaged or inhibited in their replication, or in cases of severe cell loss.
Hepatic progenitor cell activation has been described in various acute and chronic liver diseases. Their niche is composed by numerous cells such as Hepatic Stellate Cells, endothelial cells, hepatocytes, cholangiocytes, Kupffer cells, pit cells and inflammatory cells. All these cells, numerous hormones and growth factors could interact and cross-talk with progenitor cells influencing their proliferative and differentiative processes. Hepatic progenitor cells and their niche could represent, in the near future, a target for therapeutic approaches to liver disease based on cell-specific drug delivery systems.
Isolation and transplantation of hepatic progenitor cells could represent a new approach for therapy of end-stage chronic liver diseases, as they offer many advantages to transplantation of mature hepatocytes. The possibility of applying stem cell therapy to liver diseases will represent a major goal in this field.
Keywords: Estrogens, Hepatic progenitor cells, Isolation, Niche
1. Introduction
A stem cell could be defined as a cell that can continuously produce unaltered daughter cells and that also has the ability to produce cells with different, more restricted proprieties. The term “Progenitor Cell” represents a generic term used to indicate any dividing cell with the capacity to differentiate. Every progenitor cell could give rise to a progeny composed of transit-amplifying cells fated for differentiation or initially not committed and retaining self-renewal capabilities [1].
In adult livers, a progenitor (stem) cell compartment has been identified and investigated as a possible therapeutic target for liver regeneration [2].
2. Hepatic progenitor cells
Hepatic progenitor cells (or HPCs) are bi-potential stem cells residing in human and animal livers that are able to differentiate towards the hepatocytic and the cholangiocytic lineages [2], [3]. This compartment has been called the progenitor (in humans) or the oval cell compartment (in rodents) and it resides in the canals of Hering (Fig. 1). These canals represent the smallest and most peripheral branches of the biliary tree connecting the bile canalicular system with interlobular bile ducts [4].
Fig. 1.
Location of hepatic progenitor cells niche within the liver. Progenitor cells are located in the canals of Hering which represent the connection between bile canaliculi and bile duct systems.
The bile produced by hepatocytes is initially secreted into the bile canaliculi which are located between the cytoplasmic membranes of two adjacent hepatocytes. Bile canaliculi are connected with bile ducts through the interposition of the canals of Hering. At the level of the ductular–canalicular junction, the lumen of the biliary tree is partially lined with hepatocytes and cholangiocytes. Therefore, the canals of Hering represent the anatomical and physiologic link between hepatocyte canaliculi and the biliary duct systems [4], [5].
In the normal liver, HPCs are small cells with an oval nucleus and scant cytoplasm. In routine histomorphological stainings such as Haematoxylin & Eosin, they would be hardly recognizable on the basis of their shape; therefore, several immunohistochemical markers have been used to readily recognize these cells: cytokeratin (CK)-7 and CK-19 represent the most reliable and accepted markers. These intermediate filaments of the cytoskeleton are also typically expressed by mature cholangiocytes of interlobular bile ducts. HPCs can also express proteins in common with mature hepatocytes (albumin, CK-8), immature foetal hepatoblasts (α-fetoprotein), haematopoietic stem cells (CD133, c-Kit) and neuroepithelial cells (Neural Cell Adhesion Molecule) [6], [7], [8].
The differentiation of Hepatic Progenitor Cells towards mature hepatocytes or cholangiocytes is characterized by the appearance of cells with intermediate phenotypes which represent a trans-amplifying population (Fig. 2). In particular, during the differentiation towards mature hepatocytes, the progenitors give rise to intermediate hepatocytes, polygonal cells with a size intermediate between that of HPCs and mature hepatocytes; on the other hand, the HPCs differentiation towards mature cholangiocytes determines the appearance of immature cholangiocytes [3], [6], [7], [9]. The maturation from HPCs to cholangiocyte could occur through differentiation into small and then large cholangiocytes, moving from the canal of Hering to the bile ductules and the larger ducts; however, evidence for this exists only in rodents [3], [6], [7], [9].
Fig. 2.
Differentiation of hepatic progenitor cells towards mature hepatocytes or cholangiocytes. This process is characterized by the appearance of trans-amplifying populations represented by intermediate hepatocytes and reactive ductules.
Hepatic progenitor cells represent a dynamic cellular compartment that continuously changes morphology and phenotype in correlation with differentiation. The acquisition of an intermediate trans-amplifying phenotype is characterized by the modification of immunohistochemical markers. In particular, the differentiation towards the hepatocytic lineage is characterized by the progressive loss of biliary cytokeratins. In fact, the cytoplasm of intermediate hepatocytes is negative for CK-19 and faintly positive for CK-7, with immunoreactivity most pronounced near the cell membrane. Finally, the full maturation into hepatocytes determines the complete disappearance of biliary markers. By contrast, immature cholangiocytes maintain CK-7 and CK-19 expression until fully differentiated into mature cells, which are characterized by the disappearance of neuroendocrine markers such as NCAM or Chromogranin-A [6], [10].
It is currently thought [11] that, in the adult liver, HPCs represent remnants of the ductal plate (in foetal liver), which is a formation emerging during liver development as part of an angiogenesis/vasculogenesis process. It is generated from the primitive hepatoblasts adjacent to the mesenchyme around the largest portal vein branches. The ductal plate found in foetal and neonatal livers transitions to become the canals of Hering in pediatric and adult livers. Thus, the canals of Hering seem to be the adult remnants of the ductal plates giving rise to bipotent HPCs [11]. Some authors indicate the possibility that the stem cells residing in the ductal plate of the foetal liver and in the canals of Hering of the adult liver are pluripotent stem cells which generate bi-potential hepatoblasts [11].
3. Activation of HPCs
In adult livers, hepatic progenitor cells are quiescent stem cells with a low proliferating rate (Fig. 3). Even when the liver responds to injuries, the cell loss and mass are normally restored through the replication of hepatocytes and cholangiocytes, since they have a near infinite capacity for self-renewal, as demonstrated in several experimental models such as partial hepatectomy or bile duct ligation [12]. In these conditions, hepatocytes or cholangiocytes of interlobular bile ducts show a high proliferating rate and are responsible for the restoration of liver or the increasing of bile duct mass, respectively. Therefore, hepatic progenitor cells represent a reserve compartment that is activated only when the mature epithelial cells of the liver are continuously damaged or inhibited in their replication or in cases of severe cell loss. In these conditions, resident hepatic progenitor cells are activated and expand from the periportal to the pericentral zone giving rise to hepatocytes and/or cholangiocytes [9], [13], [14], [15].
Fig. 3.
Immunohistochemistry for cytokeratin 7 (original magnification 40×). (A) Normal human liver. Hepatic progenitor cells are located at the interface with portal space at the level of canals of Hering (arrows) and of the ductular–canalicular junction. (B) Primary biliary cirrhosis. In this pathological condition, Hepatic progenitor cells highly proliferate with the formation of reactive ductules (arrows) and intermediate hepatocytes (arrowheads).
Numerous experimental models of HPC activation after hepatocyte damage have been generated. For instance, the combination of partial hepatectomy with the administration of substances capable of inhibiting the replication of hepatocytes (such as ethionine, 2-acetylaminofluorine and 3-methyl-4-dimethyl aminobenzene) could determine a massive activation of the progenitor cell compartment [9]. In these models, two distinct patterns of HPC activation have been observed in relation with an acute or chronic injury. In particular, the administration of a high dose of 2-acetylaminofluorene (AAF) determines an acute response consisting of a massive proliferation of progenitor cells penetrating deep into the liver lobule though most of them do not differentiate. On the other hand, the use of a low dose of AAF is able to mimic a chronic liver injury and induces a less pronounced activation of the HPC compartment; this experimental procedure determines a higher differentiation rate in progenitor cells and numerous reactive ductules penetrate into the liver lobule and differentiate simultaneously into intermediate hepatocytes [9].
Less is known in regard to the role of progenitor cells in experimental models of biliary diseases. In BDL rats and mice, the ligation of extra-hepatic bile ducts, determines the proliferation of cholangiocytes of medium and large bile ducts, which leads to an increase in bile duct mass [12]. Until now, no experimental models have been generated in which a prominent proliferation of progenitor cells is induced.
4. Hepatic progenitor cells in human liver pathologies
Since almost all human liver diseases are characterized by a certain degree of damage, loss and impaired regeneration of hepatocytes and/or bile ducts, it is not surprising that HPC activation has been described in various conditions (Fig. 3). This activation is characterized by the appearance of reactive ductules (ductular reaction). Reactive ductules are anastomosing strands composed by progenitor cells with highly variable marker profiles, in which intermediate cells of several differentiation states are continuously produced [4]. Ductular reaction is composed by undifferentiated progenitor cells and HPCs committed towards hepatocytic and/or cholangiocytic lineages [16].
A prominent proliferation of the progenitor compartment is present in liver regeneration after acute massive necrosis of hepatocytes. Similarly, a significant HPC activation has also been described in the advanced stages of the majority of chronic human liver diseases [2], [17], [18].
Recently, it has been demonstrated that a threshold of a 50% loss of hepatocytes, together with a significant decrease in proliferation of the remaining mature hepatocytes, is required for an extensive HPC activation. In this setting, HPC proliferation occurs within 1 week, and their differentiation into hepatocytes starts after 2 weeks; moreover, HPC activation positively correlates with clinical parameters of disease severity such as the MELD score, and can influence the prognosis of this pathological condition [18]. The inhibition of hepatocyte replication also occurs in long-term chronic liver diseases, and is associated with HPC activation. In several chronic liver pathologies, the extent of HPC proliferation is correlated with the extent of fibrosis [19].
Moreover, in chronic viral hepatitis, the activation and localization of HPCs are also correlated with the severity and the localization of the inflammatory infiltrate. In moderate-to-severe lobular inflammation, progenitor cells were strikingly scattered throughout the parenchyma and were surrounded by intermediate hepatocyte-like cells, suggesting the migration of progenitor cells away from the portal periphery into the lobular parenchyma, where they differentiate towards hepatocytes [19].
There are only a few human liver diseases in which HPC activation does not take place. It does not occur after acute and complete extrahepatic biliary obstruction, which is most commonly caused by bile stones. The ductular proliferation that occurs in this condition is fundamentally different from the ductular reaction in other liver diseases, since it is the result of the proliferation of mature cholangiocytes without the involvement of HPCs. By contrast, a prominent HPC involvement has been described in chronic biliary diseases such as Primary Biliary Cirrhosis (PBC), even if less information is available regarding its role during the clinical and pathological evolution of this disease [20].
PBC represents a typical biliary disease, in which cholangiocytes are the primary target of an autoimmune response resulting in a progressive loss of bile ducts, leading to ductopenia [21]. This progressive loss is caused by apoptotic cell death that is, in earlier stages, compensated by the proliferation of residual cholangiocytes. In the advanced stages, cholangiocyte proliferation is severely impaired and the relative predominance of apoptosis leads to ductopenia [22], [23].
The possible role of progenitor cell activation in the evolution and pathogenesis of PBC is still not clearly evident. In the advanced stages, a massive activation of HPCs can be detected. Strands of reactive ductules are located in the fibrotic septa and at the interface with cirrhotic nodules surrounded by hepatic stellate cells (Fig. 4) [2], [16].
Fig. 4.
Triple immunofluorescence staining for cytokeratin 7 (Blue), cytokeratin 19 (Red) and α-smooth muscle actin (Green). Primary biliary cirrhosis (original magnification 20×). Numerous reactive ductules are surrounded by hepatic stellate cells/myofibroblasts (arrows). Most of these cells are positive for cytokeratin 7 and 19 indicating an undifferentiated phenotype.
This prominent ductular reaction is composed of progenitor cells with highly variable marker profiles in which intermediate cells of several differentiation states are present. Most of these cells are undifferentiated or committed towards cholangiocytic lineage [16].
5. Hepatic progenitor cells niche and its role in HPCs activation
A stem cell niche is defined as the cellular and extracellular microenvironment which supports stem cells and contributes to sustain self-renewal [24]. The interaction with the specific microenvironmental cells is thought to be a key mechanism in regulating the maintenance of self-renewal and differentiation capacities by stem cells. Nevertheless, a number of different types of signalling and adhesion molecules within the niche could influence stem cell quiescence, self-renewal and cell fate decisions. In fact, the stem cell niche has been attributed functions such as (i) the maintenance of stem cell quiescence and (ii) the provision of proliferation or differentiation-inducing signals when numerous progenitor cells are required to give rise to transit-amplifying cells committed to producing mature cell lineages [11], [24], [25], [26].
In stem cell niches of numerous organs (such as bone marrow, intestine and brain), Wnt, Notch and Hedgehog signals function together to maintain stem cell quiescence, to control proliferation and to govern cell fate decisions. In particular, the Wnt and Notch signalling pathways combine to control the detailed pattern of cell fate choices as stem cells divide and give rise to differentiated progeny [26].
In the liver, the hepatic progenitor cell niche is located at the level of the canals of Hering and is composed of numerous different cells such as portal myofibroblasts (MF)/Hepatic Stellate Cells (HSCs), endothelial cells, hepatocytes, cholangiocytes, Kupffer cells, pit cells and inflammatory cells. All these cells could interact and cross-talk with HPCs influencing their proliferative and differentiative processes through the provision of numerous signals within the niche [27]. It has been reported that the autocrine and paracrine Wnt secretion is clearly involved in the hepatic progenitor cell response in mice, rats and humans [28], [29], [30], [31]. Hedgehog signalling represents a required factor for survival of HPCs through the activation of the specific receptor Patched (PTC) expressed by progenitors [31].
Moreover, inflammatory cells are responsible for producing a range of cytokines and chemokines that could influence the HPC response to liver injury [27]; for instance, T cells express a TNF-like weak inducer of apoptosis (TWEAK) which can stimulate HPC proliferation by engaging its specific receptor. Other elements of the inflammatory response (such as lymphotoxin-β, IFNγ, TNFα and even histamine) may stimulate hepatic progenitor cells [32], [33]. Moreover, a resistance to the growth-inhibitory effects of TGF β has been postulated to allow HPCs to proliferate under conditions which would inhibit hepatocyte proliferation [34].
It is now clear that there is an intimate cross-talk between HPCs and hepatic stellate cells [14], [35], [36]. HSCs are a major source of growth factors, such as transforming growth factor alpha, hepatocyte growth factor, and acidic fibroblast growth factor. In particular, a close correlation between the degree of hepatocellular injury, HPC expansion and fibrosis has been noted in numerous human liver diseases such as viral hepatitis, steatohepatitis and Primary Biliary Cirrhosis (Fig. 4). HPCs can be directly responsible for stellate cell activation and fibrosis or, vice versa, activated stellate cells could promote HPC expansion and drive their differentiation. In addition, the stimulation of the HPCs and stellate cells could occur independently but in tandem, through similar mediators or stimuli [37]. A recent study on animal models by Van Hul et al. [38] seems to indicate that HPCs need a support matrix, presumably provided by myofibroblasts/HSCs, for migration and anchorage, in order to differentiate and repopulate the damaged liver. This observation reinforces the hypothesis of a fundamental role for the niche compounds in HPC proliferation and differentiation. Further studies are required to understand the mechanisms for the interactive cross-talk between HPCs, associated myofibroblasts and the extracellular matrix in human diseases [38].
Most significantly, even less is known about the functions of specific growth factors or hormones in the expansion of the progenitor cells niche. Numerous previous studies, nicely reviewed by Glaser et al. [39], have proven that the proliferation of cholangiocytes is regulated by several substances such as steroid hormones (i.e., estrogens, progesterone), growth factors such as Insulin-Like Growth Factor 1 (IGF1), and Vascular Endothelial Growth Factor (VEGF), bile acids and neurotransmitters (acetylcholine). These substances play a key role in the regulation of cholangiocyte proliferation during liver injury [40], [41]. For instance, cholangiocytes represent a target for estrogens and the IGF1 axis which play a major role in cholangiocyte resistance to apoptotic cell death, and influence the survival of residual cholangiocytes in PBC stage IV [22], [23]. Moreover, cholangiocytes are able to release autocrine and paracrine factors that regulate proliferation and activate fibrogenic response of portal myofibroblasts and hepatic stellate cells, resulting in activating fibrogenesis. In addition, cholangiocytes can undergo epithelial-mesenchymal transition and increase the number of fibrogenic cells in the portal areas [39]. Conversely, the role of these substances in the modulation of the progenitor cell compartment, and the possible cross-talk between HPCs and cholangiocytes have still not been assessed.
The understanding of the autocrine and paracrine pathways that regulate cholangiocyte and progenitor cell proliferation during the progression of liver diseases could open the possibility for the development of therapeutic strategies. The HPC compartment could represent an important target for new therapeutic approaches to liver diseases through a correct pharmacological modulation.
6. Isolation of HPCs and their possible use in end-stage chronic liver diseases
Given their biological properties, isolation and transplantation of hepatic progenitor cells could represent a new therapeutic approach for end-stage chronic liver diseases [42], [43], [44].
The use of stem/progenitor cells may have several advantages in comparison with transplantation of mature hepatocytes. Hepatocyte transplantation has been performed for more than 10 years in humans meeting with varied degrees of success [44], [45]. The general problems for hepatocyte cell-based therapies have been the limited repopulation capacity of grafted cells, and that they are easily damaged during the freezing–thawing procedure. Therefore, transplantation of mature hepatocytes in the setting of acute liver failure can only be viewed as a bridge to liver transplantation, since it can improve the metabolic status of extremely ill patients [44], [45].
Grafting stem/progenitor cells could determine a better long-term repopulation and a more persistent metabolic activity due to the constant generation of newly formed hepatocytes. However, numerous issues remain to be addressed before progenitor cells can be used in clinical practice.
Isolation of hepatic progenitor cells from human material has proven to be very difficult. In fact, although several markers are expressed by HPCs, their unequivocal isolation as a pure fraction has been a major obstacle in liver progenitor cell research [46]. Hepatic progenitor cells represent a dynamic cellular compartment that continuously changes morphology and phenotype in correlation with their differentiation. Moreover, none of the described markers are completely specific or are surface proteins, thus limiting their use for isolation of viable cells [6], [7].
Different clinically relevant populations of hepatic stem/progenitor cells have been recently isolated from non-damaged foetal and/or adult human livers using Epithelial Cell Adhesion Molecule (EpCAM) or Thymus cell antigen 1 (Thy-1) as markers for sorting progenitor cells from human livers [47], [48].
Schmelzer et al. have demonstrated that purified EpCAM+ cells from foetal or postnatal livers are able to engraft the livers of immunodeficient adult mice (with or without prior injury) and to give rise to mature human liver parenchymal cells. The efficiency of the isolation of EpCAM+ cells from human livers, the demonstration of their pluripotency and the evidence that they can generate mature liver tissue after transplantation are encouraging for clinical use [47]. Similar results have been obtained by Weiss et al. through the isolation of Thy-1+ cells from adult human livers and their transplantation in a mouse model [48].
However, the exact phenotype of the isolated hepatic progenitor cells still remains unclear; the role of alpha-fetoprotein to distinguish between adult progenitor cells and hepatoblasts seems to be controversial, since this marker is also shared by HPCs. Moreover, it has been recently demonstrated that Thy-1, initially introduced as a marker of progenitor cells, is not expressed by the HPCs themselves but by the neighbouring HSCs or progenitors of the mesenchymal lineage [49].
Finally, the suitability of hepatic progenitor cells for hepatic repopulation in the clinical setting still needs to be assessed. In fact, a major obstacle in the transplantation of HPCs in human patients and in their application in clinical trials is represented by the production of these cells in the respect of strict Guidelines and Laws. As recently suggested, the standardization of the processes from basic research to the development of clinical trials will be essential to ensure cell-based therapies for chronic liver diseases [44]. This process will include the use of standardized methodologies to characterize the cells to be grafted using a standard set of phenotypic markers, as well as a standard set of in vitro functional studies. Animal models should be used for preclinical assessment of the repopulation ability of hepatic progenitor cells or their capability to differentiate into a progeny able to functionally replace liver cell loss. Finally, clinical trials using hepatic stem/progenitor cells or their differentiated progeny should be planned, with the development of standardized protocols for standardized procedures to define the nature of cells, the patients enrolled, the transplantation procedure and pre-treatment of the liver, as well as standard data collection regarding efficacy, and possible side effects [44].
7. Concluding remarks
Hepatic progenitor cells represent nowadays a key target for developing new therapeutic approaches for liver diseases. HPCs represent a reserve stem cell compartment that could be stimulated and driven to differentiate through a cell-targeted pharmacological modulation. Signals that govern HPC proliferation and differentiation into mature parenchymal liver cells are still not clarified and understood as well as the role of the niche in the modulation of the resident progenitor cell compartment.
Moreover, the shortage of liver donors and the well-known limits of liver transplantation underscore the need and the possibility of applying a stem cell therapy to end-stage chronic hepatic diseases and to acute massive liver injury. The transposition of isolation strategies to clinical trials will represent a major goal in this field.
Conflict of interest statement
The authors declare that there is no conflict of interest connected to the present manuscript.
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PII: S1590-8658(09)00151-0
doi:10.1016/j.dld.2009.03.009
© 2009 Published by Elsevier Inc.
