Bile Acids and Liver Regeneration Dig Dis 2015;33:332–337 DOI: 10.1159/000371673

Bile Acids and Stellate Cells Claus Kordes Iris Sawitza Silke Götze Dieter Häussinger Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University, Düsseldorf, Germany

Abstract Hepatic stellate cells are mainly known for their contribution to fibrogenesis in chronic liver diseases, but their identity and function in normal liver remain unclear. They were recently identified as liver-resident mesenchymal stem cells (MSCs), which can differentiate not only into adipocytes and osteocytes, but also into liver epithelial cells such as hepatocytes and bile duct cells as investigated in vitro and in vivo. During hepatic differentiation, stellate cells and other MSCs transiently develop into liver progenitor cells with epithelial characteristics before hepatocytes are established. Transplanted stellate cells from the liver and pancreas are able to contribute to liver regeneration in stem cell-based liver injury models and can also home into the bone marrow, which is in line with their classification as MSCs. There is experimental evidence that bile acids support liver regeneration and are able to activate signaling pathways in hepatic stellate cells. For this reason, it is important to analyze the influence of bile acids on developmental fate decisions of hepatic stellate cells and other MSC populations. © 2015 S. Karger AG, Basel

© 2015 S. Karger AG, Basel 0257–2753/15/0333–0332$39.50/0 E-Mail [email protected]

Hepatic Stellate Cells

Hepatic stellate cells can produce extracellular matrix proteins and are mainly known for their contribution to fibrosis in chronic liver diseases [1]. Since molecular markers of different germ layers are simultaneously present in hepatic stellate cells [2], their origin and identity have remained unclear. For instance, neuroectodermal proteins in stellate cells such as glial fibrillary acidic protein (GFAP) [3, 4] led to the view that they may derive from the neural crest, but recent studies have indicated a mesodermal origin of stellate cells [5, 6]. During liver development, stellate cells initially exhibit myofibroblastlike features, and typical perisinusoidal reticular networks by stellate-shaped cells with long cellular extensions are gradually intensified when the liver tissue is established [5]. This indicates that the myofibroblast-like phenotype is a transient state of stellate cells. In the adult rodent liver, the stellate cell network can be visualized by immunostaining of the intermediate filament proteins desmin and GFAP [3, 7]. The presence of GFAP at the protein level is typical for quiescent hepatic stellate cells (fig. 1a) and the expression of GFAP gradually increases after liver development [8], whereas the mesodermal marker protein desmin occurs in the majority of freshly isolated stellate cells and significantly increases during their activation in culture. The normal human liver lacks desmin expression in stellate cells, whereas GFAP is only observed in a small subpopulation of stellate cells around Prof. Dr. Dieter Häussinger Clinic of Gastroenterology, Hepatology and Infectious Diseases Heinrich Heine University, Moorenstrasse 5 DE–40225 Düsseldorf (Germany) E-Mail haeussin @

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Key Words Hepatic stellate cells · Mesenchymal stem cells · Liver regeneration · Bile acids




the portal tracts. However, desmin becomes detectable along with α-smooth muscle actin in a subset of human stellate cells in diseased liver [9, 10], demonstrating difficulties in the identification of stellate cells in humans when these filament proteins are used as markers. Another and more robust indicator for quiescent hepatic stellate cells is their retinyl palmitate content. The retinoid stores in membrane-coated lipid vesicles, which show autofluorescence after excitation with ultraviolet light, can also be observed in stellate cells from other organs, but the retinoid amounts are exceptionally high in hepatic stellate cells.

Hepatic Stellate Cells as Liver Resident Mesenchymal Stem Cells

Retinoids influence developmental processes and have been shown to maintain the quiescent state of hepatic stellate cells [11, 12] and to preserve the immature state of hematopoietic stem cells [13] and stem cell characteristics such as the expression of nestin in mesenchymal stem cells (MSCs) [14]. One of the first events during hepatic stellate cell activation is the induction of nestin expression [15, 16], which is typically observed in activated somatic stem cells [17]. This suggests that stellate cells Bile Acids and Stellate Cells

could represent liver-resident MSCs. In line with this, stellate cells can originate from the bone marrow [18, 19], where MSCs were initially discovered, and are localized as pericytes close to the sinusoidal endothelial cells of the liver. It was supposed that MSCs occur in all organs of vertebrates as pericytes of blood vessels [20, 21]. Indeed, hepatic stellate cells of rats and mice express typical MSC markers and genes required for cell development [22– 24]. Recently, very similar gene expression was found when hepatic stellate cells and bone marrow MSCs of humans were compared. In addition, stellate cells can also fulfill pivotal functions of bone marrow MSCs since stellate cells support hematopoietic stem cells and blood formation in vitro and are associated with hematopoietic sites when blood formation takes place in the fetal liver [25]. MSCs are important elements of the hematopoietic stem cell niche in the bone marrow and their depletion decreases hematopoiesis [26, 27]. For a long time it was not clear if MSCs themselves require a niche to maintain their characteristics. Now the perivascular zone is supposed to represent the MSC niche in vivo [20]. In the liver parenchyma, the space of Disse is a unique perisinusoidal space with a basement membrane-like matrix delineated by fenestrated sinusoidal endothelial cells and hepatocytes. Hepatic stellate cells reside in the space of Dig Dis 2015;33:332–337 DOI: 10.1159/000371673


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late cells from rats are retinoid-storing cells (lipid droplets), which express GFAP (red; color in online version only) in their quiescent state [1, 3]. Isolated hepatic stellate cells can differentiate into adipocytes (b) (cells with lipids) that express fatty acidbinding protein 4 (FABP4; red; insert) and into osteocytes (c) which are characterized by fine cellular processes and the expression of osteocalcin (red; insert) [25]. This differentiation potential is frequently used to characterize MSCs from various tissues. d Moreover, isolated hepatic stellate cells can also differentiate into epithelial liver cells such as hepatocytes, which typically express keratin 18 (red), when they are treated with growth factors in vitro [35]. The presence of the mesodermal filament protein desmin (green) in keratin 18-expressing cells indicates their origin from hepatic stellate cells.

Color version available online


Fig. 1. Developmental potential of hepatic stellate cells. a Freshly isolated hepatic stel-


Dig Dis 2015;33:332–337 DOI: 10.1159/000371673

in hepatic stellate cells and MSCs of the bone marrow [41, 42]. Also the support of hematopoietic stem cells by hepatic stellate cells or bone marrow MSCs in coculture experiments is apparently mediated through the release of soluble factors or direct cell-cell contacts [25]. Similar to bone marrow MSCs, hepatic stellate cells seem to fulfill a dual role as modulatory or supportive cells on the one hand and as direct precursor cells on the other (fig. 2). Their function in regenerative processes is most likely context-dependent and may explain the conflicting experimental outcomes when different animal and injury models were applied. In chronic diseases, however, the activity of stellate cells and bone marrow MSCs can also exert deleterious effects through the deposition of extracellular matrix proteins and development of fibrotic tissue [1, 43, 44].

Effects of Bile Acids on Hepatic Stellate Cells

Bile acids are not only involved in fat absorption in the intestine but are also pivotal signaling molecules by stimulating the nuclear farnesoid X receptor (FXR) or transmembrane G protein-coupled receptor (TGR5). Bile acids are also important mediators of liver regeneration since cholic acid-enriched chow (0.2%) can promote liver regrowth after partial hepatectomy in mice via FXR-dependent mechanisms [45]. In contrast to this, elevated bile acid concentrations in cholestatic liver disease have adverse effects by inducing apoptosis and necrosis of hepatocytes, but hepatic stellate cells can survive under these circumstances [46, 47]. They are resistant to bile acid-mediated apoptosis and show increased DNA synthesis and cell proliferation in response to elevated bile acid concentrations via epidermal growth factor receptor-mediated signaling [46, 47]. It appears that stellate cells are primed to survive in order to ensure wound healing and regeneration of the liver even under adverse conditions. In cholestatic liver disease, bile acids promote the development of liver fibrosis [46], but FXR ligands are also suggested as a therapeutic option to treat liver fibrosis. The production of an extracellular matrix decreased in animal models of fibrosis and in isolated hepatic stellate cells after 6-ethyl-chenodeoxycholic acid treatment [48]. However, the antifibrotic effects of FXR ligands as therapeutic agents are still under discussion. Interestingly, FXR stimulation is known to control developmental fate decisions of bone marrow MSCs [49], indicating that bile acid signaling via FXR may also influence the differentiation of stellate cells. Kordes/Sawitza/Götze/Häussinger

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Disse, which provides elements that preserve their characteristics, indicating that the space of Disse serves as a niche for stellate cells in the liver [28, 29]. In addition to the expression pattern, which can vary among MSCs from different organs, MSCs are usually characterized by their developmental potential. MSCs are multipotent cells that typically differentiate into bone, fat and cartilage cell lineages. Indeed, hepatic stellate cells isolated from rats and the human hepatic stellate cell line LX-2 can become adipocytes and osteocytes in vitro when they are treated with suitable differentiation media (fig. 1b, c) [25, 30]. Moreover, stellate cells can develop into liver parenchymal cells in vitro after treatment with hepatocyte growth factor and fibroblast growth factor 4 (fig. 1d) [22]. This finding indicated the potential of stellate cells to contribute to liver regeneration. Indeed, cell lineage-tracing and transplantation studies confirmed that stellate cells can differentiate into epithelial liver cells such as hepatocytes and bile duct cells also in vivo [31– 35]. Transplanted stellate cells can substantially contribute to tissue repair in stem cell-based liver regeneration models when the proliferation of mature hepatocytes is impaired by toxic substances, such as 2-acetylaminofluorene or retrorsine, and the liver is injured by partial hepatectomy. Transplanted stellate cells form mesenchymal and epithelial tissue within the injured host liver [32, 35]. Transient development of hepatobiliary progenitor cells can be observed during hepatic differentiation of stellate cells and MSCs from the bone marrow and umbilical cord blood [35], which demonstrates that MSCs from various sources behave in a similar way. Although the participation of mesodermal cells in epithelial tissue regeneration still remains controversial, compelling evidence exists that MSCs from bone marrow or adipose tissue can contribute to liver repair through differentiation [36–38]. This direct involvement of MSCs in the recovery of epithelial cells certainly depends on the severity of tissue injury since epithelial cells such as parenchymal cells are known to mediate liver regeneration in the first place. However, engraftment of transplanted stellate cells from the liver and pancreas can also be found in bone marrow, which further supports their classification as MSCs (fig. 2) [32, 35]. There is accumulating evidence that bone marrow MSCs and stellate cells can also participate in regenerative processes through the release of growth factors, cytokines and chemokines in order to guide the behavior of neighboring cells [39, 40]. For example, immunomodulatory activity by T-cell suppression was congruently found

liver injury as well as tissue homeostasis. Hepatic stellate cells are mainly known for their contribution to fibrosis in chronic liver diseases. They can deposit extracellular matrix proteins such as collagens, but also promote blood vessel growth [1]. After acute liver injury, hepatic stellate cells may support proliferating hepatocytes and progenitor cells by the release of growth factors such as hepatocyte growth factor. During stem cell-based liver regeneration, hepatic stellate cells also differentiate into hepatocytes and bile duct cells, which involve the transient formation of progenitor

cells [35]. Transplantation studies have revealed that hepatic stellate cells can home into the bone marrow of host animals [35], but also cells from the bone marrow are capable of becoming stellate cells after engraftment in the host liver [18, 19]. Little information is available about functions of stellate cells in normal liver. In the fetal liver, stellate cells are involved in hematopoiesis support [25] and in the normal adult liver they could play a role as modulators of the immune system. However, the immunomodulatory function of hepatic stellate cells is pronounced when they are derived from fibrotic livers [42].

Some groups have been able to detect FXR in stellate cells [48], but others have failed, which may explain some of the uncertainness in this field. TGR5 is also expressed by hepatic stellate cells, but only when they become activated [50]. Even modified bile acids such as 24-nor ursodeoxycholic acid with weak or no binding to FXR and TGR5 are reported to exhibit antifibrotic effects [51], suggesting

that mechanisms independent of these bile acid receptors control the behavior of myofibroblast-like cells. In hepatic stellate cells, conjugated and unconjugated bile acids can rapidly induce early growth response (EGR) and FBJ osteosarcoma antigen (FOS) gene expression apparently via protein kinase C and mitogen-activated protein kinase activation [52]. Interestingly, EGR1 is essen-

Bile Acids and Stellate Cells

Dig Dis 2015;33:332–337 DOI: 10.1159/000371673


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Color version available online

Fig. 2. Functions of hepatic stellate cells during acute and chronic

tial to maintain hematopoietic stem cells in their niche within the bone marrow and its knockout elevates blood formation [53], whereas other EGR variants are supposed to be involved in regenerative and fibrotic processes. In the liver, EGR1-deficient mice show decreased fibrosis after chemical-induced liver injury and the appearance of progenitor cells, suggesting that EGR1 is an important antifibrotic regulator [54, 55]. The data available thus far strongly indicate that hepatic stellate cells and myofibroblasts are targets of bile acids. It will be interesting to analyze whether bile acids can influence cell differentiation and control developmental fate decisions in stellate cells.

Acknowledgement The authors are grateful to the German Research Foundation (Deutsche Forschungsgemeinschaft) for the financial support through the Collaborative Research Center 974 (SFB 974) ‘Communication and Systems Relevance during Liver Injury and Regeneration’.

Disclosure Statement The authors have nothing to declare.



Dig Dis 2015;33:332–337 DOI: 10.1159/000371673

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Bile acids and stellate cells.

Hepatic stellate cells are mainly known for their contribution to fibrogenesis in chronic liver diseases, but their identity and function in normal li...
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