Abstract
Recent evidence indicates that the plasticity of preexisting hepatocytes and bile duct cells is responsible for the appearance of intermediate progenitor cells capable of restoring liver mass after injury without the need of a stem cell compartment. However, mesenchymal stem cells (MSCs) exist in all organs and are associated with blood vessels which represent their perivascular stem cell niche. MSCs are multipotent and can differentiate into several cell types and are known to support regenerative processes by the release of immunomodulatory and trophic factors. In the liver, the space of Disse constitutes a stem cell niche that harbors stellate cells as liver resident MSCs. This perivascular niche is created by extracellular matrix proteins, sinusoidal endothelial cells, liver parenchymal cells and sympathetic nerve endings and establishes a microenvironment that is suitable to maintain stellate cells and to control their fate. The stem cell niche integrity is important for the behavior of stellate cells in the normal, regenerative, aged and diseased liver. The niche character of the space of Disse may further explain why the liver can become an organ of extra-medullar hematopoiesis and why this organ is frequently prone to tumor metastasis.
Introduction: liver regeneration
The liver has an outstanding regenerative capacity, which normally relies on the proliferation of hepatocytes and non-parenchymal cells after loss of liver mass (Michalopoulos and DeFrances, 1997). When the proliferation of hepatocytes is impaired, liver progenitor cells (LPC) seem to be involved in the reconstitution of liver tissue. LPC can be detected in diseased human and rodent liver and are induced in certain injury models (Wilson and Leduc, 1958; De Vos and Desmet, 1992). For instance, LPC, which are called oval cells in rodents, are inducible in rats after surgical removal of the two largest liver lobes (70% of the liver; partial hepatectomy) and simultaneously restricted hepatocyte proliferation by 2-acetylaminofluorene intoxication (Tatematsu et al., 1984). These LPC can contribute to liver regeneration through differentiation into hepatocytes and bile duct cells (cholangiocytes) in the case of severe liver damage (Michalopoulos and Khan, 2005). However, the origin and function of LPC during repair of an injured liver is not completely resolved and has been controversially discussed (Kordes and Häussinger, 2013; Michalopoulos and Khan, 2015; Kopp et al., 2016). Several studies indicate that LPC emanate from the portal field and seem to derive from putative stem cells within the canals of Hering, which are the most proximal branches of the biliary tree consisting of cholangiocytes and parenchymal cells (Theise et al., 1999; Dorell et al., 2011; Furuyama et al., 2011; Espanol-Suner et al., 2012; Miyajima et al., 2014). In addition, thymus cell antigen 1 (THY1/CD90)-positive bone marrow cells and hepatic stellate cells are facultative sources of LPC (Petersen et al., 1999; Kordes et al., 2014). To add further complexity, monitoring of pericentral cells that express the WNT target gene Axin2 suggest that the liver tissue is slowly replenished over time by hepatocytes that derived from precursor cells close to the central vein (Wang et al., 2015). Thus, two different sites for new hepatocytes are suggested, one for homeostatic renewal (central vein) and one for tissue restoration after severe liver injury (portal field).
Recent studies indicate that the contribution of LPC to the reconstitution of liver mass largely depends on the severity of tissue injury in rodent models (Chien et al., 2018), which may explain discrepant observations in the past. Moreover, cholangiocytes, which share markers with LPC, have been identified as facultative LPC capable of restoring hepatocytes only if the proliferation of parenchymal cells is permanently suppressed (Raven et al., 2017). Hepatocytes have also been shown to contribute to LPC in vitro and in vivo using animal models of chronic liver injury (Chen et al., 2012; Tarlow et al., 2014). Recent findings suggest a fetal reprograming of hepatocytes that leads to LPC which is dependent on yes-associated protein-1 (YAP1) and insulin-like growth factor-2 RNA-binding protein-3 (IGF2BP3) (Hyun et al., 2019). It seems that the high plasticity of preexisting epithelial cells (i.e. hepatocytes and cholangiocytes) could explain the origin of LPC without the need of a stem cell compartment in the liver.
Stem cell niches
The stem cell niche hypothesis was developed by Raymond Schofield (Schofield, 1978) who supposed a spatially limited protective environment that maintains and controls the number of hematopoietic stem cells in the bone marrow. The first experimental evidence for the existence of stem cell niches came much later from the research of Ting Xie and Allan Spradling, who observed that germ line stem cells in Drosophila germarium require direct contacts to cap cells in order to maintain stemness (Xie and Spradling, 2000). Later on stem cell niches were also discovered in vertebrates. Besides the hematopoietic stem cell niches in the bone marrow (endosteal niche, vascular niches at arterioles and sinusoids), stem cell niches are present in the hair follicles (bulge), gut crypts, gonads, skeletal muscle fibers, subventricular and subgranular zones of the brain, as comprehensively reviewed elsewhere (Morrison and Spradling, 2008; Goldman and Chen, 2011; El-Hayek and Clarke, 2016; Gonzales and Fuchs, 2017; Yoshida, 2018; Schmidt et al., 2019). Important components of stem cell niches are neighboring cells that interact with the stem cells by establishing direct cell-cell contacts and release of soluble factors (chemokines, WNT ligands, growth factors, etc.), extracellular matrix composition, physical factors (substrate elasticity, shear forces), low oxygen-tension and metabolism (Morrison and Spradling, 2008); Marthiens et al., 2010; Nishimura et al., 2010; Lane et al., 2014). To enable communication with distant organs and to control stem cell recruitment, a contact of niche cells to the peripheral nervous system was also been reported (Katayama et al., 2006). However, the presence of a stem cell ultimately defines the stem cell niche.
Mesenchymal stem cells
The term ‘mesenchymal stem cell’ (MSC) was originally created by Arnold I. Caplan (Caplan, 1991). MSCs form a heterogenous group of somatic, multipotent stem cells first described as fibroblasts in the bone marrow that represent an important component of the hematopoietic stem cell niche (Maximov, 1906, 1928; Friedenstein et al., 1970; Kfoury and Scadden, 2015). MSCs secrete immunomodulatory and trophic factors to support regenerative processes but can also differentiate into adipocytes, osteoblasts, chondrocytes and myocytes as well as liver epithelial cells such as hepatocytes (Pittenger et al., 1999; Schwartz et al., 2002; Sato et al., 2005). Therefore, MSCs became an important research topic in regenerative medicine (Farini et al., 2014; Alfaifi et al., 2018; Spitzhorn et al., 2018). Moreover, MSCs are pivotal elements for the hematopoietic stem cell niche in the bone marrow and their depletion by experimental intervention or aging impairs blood formation (Eaves et al., 1991; Méndez-Ferrer et al., 2010; Maryanovich et al., 2018). However, MSCs are not restricted to the bone marrow but rather occur in all organs and are associated with blood vessels (da Silva Meirelles et al., 2006; Crisan et al., 2008). For a long time, it was not clear, whether MSCs themselves require a niche to maintain their characteristics. Now the perivascular zone is considered to be the MSC niche in vivo (da Silva Meirelles et al., 2006, 2008). If their niche is affected by aging, an altered MSC behavior and elevated expression of senescence-associated factors such as interleukin-6 are accompanied by disturbed support of hematopoietic stem cells (Li et al., 2015; O’Hagan-Wong et al., 2016; Sui et al., 2016; Maryanovich et al., 2018). Thus, maintenance of the perivascular MSC niche is essential for tissue homeostasis.
Like MSCs, pericytes are in direct contact with endothelial cells and are microscopically visible on the basement membrane of microvessels without smooth muscle cell layer (Sims, 1986). MSCs and pericytes are both multipotent cells that share many molecular characteristics and it was suggested that MSCs originate from pericytes (Caplan, 2008; da Silva Meirelles et al., 2008; Sá da Bandeira et al., 2017). Pericytes express nerve-glial antigen 2 (NG2/CSPG4/chondroitin sulfate proteoglycan 4) and nestin. They are important for angiogenesis and maintenance of blood vessel integrity and function. This is evidenced by the release of platelet-derived growth factor-B (PDGF-B) from sprouting endothelial cells sending out signals to PDGF receptor β (PDGFRβ)-expressing pericytes in a paracrine manner. Interfering with this pathway disturbs blood vessel formation by endothelial cells and developmental processes in pericytes as reviewed elsewhere (Gerhardt and Betsholtz, 2003).
Stellate cells are hepatic pericytes
Hepatic stellate cells are associated with fenestrated sinusoidal endothelial cells which constitute microvessels in the liver. At least in their quiescent state hepatic stellate cells can be clearly separated from pericytes and MSCs known from other organs, as stellate cells express glial fibrillary acidic protein (GFAP), embryonic stem cell-derived RAS (ERAS) and store fluorescent retinoids in lipid vesicles (Wake, 1971, 1980; Gard et al., 1985; Hendriks et al., 1985; Nakhaei-Rad et al., 2016) (Figures 1 and 2A,B). During their activation, however, hepatic stellate cells lose their retinoid stores, lower ERAS and GFAP expression, and acquire the expression profile of typical MSCs as indicated by the appearance of nestin, NG2 and CD44 (Niki et al., 1999; Kikuchi et al., 2005; Kordes et al., 2013; Nakhaei-Rad et al., 2016). This may indicate that hepatic stellate cells represent a quiescent state of MSCs in liver sinusoids (Figure 1). Although differences in the expression profile of isolated individual MSCs from one organ and between MSC populations from different organs are well known (Rennerfeldt and Van Vliet, 2016; McLeod and Mauck, 2017), comparative transcriptome and secretome analyses of hepatic stellate cells with pericytes and/or other MSCs demonstrate a close relationship and similar functional phenotype (Covas et al., 2008; Chinnadurai et al., 2019). The differences can originate from varying environmental cues and may reflect different states of activation or development. For instance, comparison of freshly isolated hepatic stellate cells (day 0) with culture-activated hepatic stellate cells (day 7) by transcriptome analysis results in 4066 differentially expressed genes. In contrast to this, early activated (day 3) and activated (day 7) stellate cells vary in the expression of only 420 genes (Schumacher et al., 2017). The activation process of hepatic stellate cells is accompanied by dynamic changes in epigenetics, as the global DNA methylation is lowered by 60% mainly in non-coding areas of the genome by enzyme-mediated active mechanisms and the expression profile is drastically altered to enable cell proliferation and development (Götze et al., 2015; Schumacher et al., 2017). Thus, quiescent hepatic stellate cells are silenced by epigenetic mechanisms and their direct relation to MSCs becomes visible during their activation. This explains why hepatic stellate cells were only recently identified as liver resident MSCs (Kordes et al., 2013).
Hepatic stellate cells acquire typical characteristics of MSC during activation.
Endothelial cells are covered by basement membrane proteins and associated with quiescent stellate cells in normal liver. Hepatic stellate cells share the molecular markers CD105, CD146, desmin and PDGFRβ with pericytes and MSCs known from other organs. Initially they differ from these cells, since quiescent stellate cells lack the expression of nestin, NG2, CD44 and αSMA. During their activation, however, stellate cells become positive for many molecular markers commonly used to discriminate these three cell types. (A) NG2, (B) nestin, (C) CD44 and (D) CD90 become detectable along with αSMA (not shown) in activating hepatic stellate cells at day 3–4 of culture by immunofluorescence (red). In contrast to NG2, nestin and CD44, only a small subset of activated stellate cells show CD90 at protein level. (A) The pericyte marker NG2 is transiently detectable in all activated stellate cells at day 3 but disappears at protein level during prolonged culture (not shown). Other markers such as GFAP and CD133 are downregulated during activation of hepatic stellate cells. Cell nuclei are stained by DAPI (4′,6-diamidino-2-phenylindole) (blue). The scale bars represent in (A) 50 μm and in (B–D) 20 μm.
Hepatic stellate cells in the fetal and adult rat liver.
(A) Freshly isolated hepatic stellate cells contain fluorescent retinoids in membrane-coated lipid droplets (blue) and (B) show GFAP filaments (green). (C) Scheme of the space of Disse bordered by fenestrated sinusoidal endothelial cells and hepatocytes contain extracellular matrix proteins (ECM). Stellate cells reside in this perisinusoidal space and release factors such as hepatocyte growth factor (HGF), angiopoietins (ANGPT1/2), and vascular endothelial growth factor (VEGF) to support neighboring cells and, thus, to maintain/create their own niche. Endothelial cells in turn release CXCL12 to attract stellate cells via the chemokine receptor CXCR4 and to keep them in their niche. Moreover, sinusoidal endothelial cells release WNT ligands such as WNT2 and can potentially influence stellate cell behavior. Systemic signals reach the stellate cells via the blood stream through the fenestrated endothelium and sympathetic nervous system (SNS), which release norepinephrine (NE). The perisinusoidal space of Disse between hepatocytes (CK18, green) and endothelial cells contain ECM proteins such as (D) the laminin-α5 chain (LAMA5, red) and (E) collagen 4 (COL4, red) known from basement membranes. (E) Hepatic stellate cells reside in the space of Disse and express GFAP (green). (F) Another filamentous protein typically expressed by stellate cells is desmin (green). The adult liver is normally devoid of blood-forming cells such as GATA1-positive myeloid progenitor cells (red). (G) The developing fetal liver, in contrast, is an important site for hematopoietic cells including GATA4-expressing cells (red) that are closely associated with desmin-positive stellate cells (green) within the liver sinusoids. Cell nuclei are stained by DAPI (blue). The scale bars represent 20 μm.
During liver development, stellate cells initially exhibit myofibroblast-like features and typical perisinusoidal reticular networks by stellate-shaped cells with long cellular extensions and retinoid storage becomes gradually prominent later (Enzan et al., 1997; Friedman, 2008). This indicates that myofibroblasts are a transient phenotype of stellate cells that is reversible (Kisseleva et al., 2012; Rohn et al., 2018). In the adult rodent liver, the stellate cell network can be shown by immunostaining of the intermediate filament proteins desmin and GFAP (Yokoi et al., 1984; Gard et al., 1985). The presence of GFAP protein is typical for quiescent hepatic stellate cells and increases with time during liver development, whereas nestin is expressed in their activated state (Niki et al., 1999; Suzuki et al., 2008). Another indicator for hepatic stellate cells is their retinyl palmitate content. The retinoids are stored in membrane-coated lipid vesicles, which show autofluorescence after excitation with ultraviolet light and were shown to maintain the quiescent state of hepatic stellate cells (Shiratori et al., 1987; Davis et al., 1990) (Figure 2A).
Hepatic stellate cells as stem cells
Our studies have demonstrated that stellate cells exhibit the expression pattern and functional characteristics of MSCs (Kordes et al., 2013, 2015). In line with this, stellate cells can originate from and home in the bone marrow (Baba et al., 2004; Russo et al., 2006; Kordes et al., 2014), where MSCs were originally discovered. They can also fulfill functions of bone marrow MSCs, as stellate cells are associated with hematopoietic stem/progenitor cells in the fetal liver and support in vitro hematopoiesis (Kordes et al., 2013). Stellate cells from primary culture and the human stellate cell line LX-2 can further differentiate into adipocytes, chondrocytes and osteocytes (Castilho-Fernandes et al., 2011; Kordes et al., 2013; Chinnadurai et al., 2019). These functional characteristics are frequently used to identify MSCs. Moreover, stellate cells from liver and pancreas are also transplantable and can contribute to liver regeneration in vivo through differentiation into hepatocytes and cholangiocytes (Kordes et al., 2012, 2014, 2015; Michelotti et al., 2013; Swiderska-Syn et al., 2014). Although the participation of mesodermal cells to epithelial tissue regeneration remains controversial, compelling evidence exists that MSCs from bone marrow, adipose tissue or induced pluripotent stem cells can reconstitute injured liver tissue by cell differentiation (Sato et al., 2005; Aurich et al., 2007; Chamberlain et al., 2007; Kordes et al., 2015; Spitzhorn et al., 2018). This direct involvement of MSCs in the recovery of epithelial cells may depend on the severity of tissue injury, as epithelial cells such as parenchymal cells are known to contribute to liver regeneration in the first place. As transplanted stellate cells migrate to sites of organ injury, show tissue-specific engraftment, participate in tissue repair by differentiation, and are re-transplantable, important properties of MSCs are fulfilled by stellate cells (Kordes et al., 2012, 2014). In addition, bone marrow MSCs and stellate cells can also participate in regenerative processes through the release of growth factors, cytokines, chemokines and extracellular vesicles containing miRNA to guide the behavior of neighboring cells (Caplan and Dennis, 2006; Parekkadan et al., 2007; Taura et al., 2008; Wang et al., 2010; Kordes et al., 2015; Castoldi et al., 2016). In this way MSCs are presumably permanently involved in tissue homeostasis and regeneration throughout the body.
The perivascular niche of hepatic stellate cells
The maintenance of stem cell characteristics in stellate cells requires a niche, which is provided in the liver by a unique perivascular space, the space of Disse (Sawitza et al., 2009), originally described by the German anatomist and histologist Joseph Disse. This perivascular niche contains ECM proteins and is bordered by hepatocytes and fenestrated sinusoidal endothelial cells (Figure 2C). Hepatic sinusoids lack typical pericytes known from microvessels of other organs (Sims, 1986) and it is likely that stellate cells fulfill a similar function.
Basement membrane proteins in the space of Disse
A non-electron dense basement membrane-like structure with reticular collagen 4 and laminin is present in normal liver within the space of Disse (Figure 2D, E). Laminins are composed of three laminin protein chains (α, β, γ) and recent analysis of the laminin composition of the liver has demonstrated the presence of the laminin α5 chain in hepatic sinusoids (Figure 2D). In addition to the laminin α5 chain, proteome analysis of decellularized rat liver revealed the prevalence of the laminin β1, β2, and γ1 chains (Rohn et al., 2018), suggesting that the laminin heterotrimers α5-β2-γ1 and α5-β1-γ1 are abundant in normal liver. Both heterotrimers are known to sustain self-renewal in pluripotent stem cells (Rodin et al., 2010; Laperle et al., 2015). When stellate cells are isolated from rat liver and cultured on laminin-521, their quiescent state and expression of stem cell-associated markers is promoted (Rohn et al., 2018), which emphasizes the importance of laminins for the perivascular stellate cell niche. Alterations of the composition and abundance of ECM proteins occur in liver diseases and play a role in initiating stellate cell activation and migration (Matsumoto et al., 1999; Yang et al., 2003). Moreover, the stiffness of the ECM substrate critically influences stellate cell activation (Georges et al., 2007). Thus, ECM composition and stiffness are important for the maintenance of hepatic stellate cells and alterations of the ECM in liver diseases affect the integrity of their niche (Figure 3).
The niche integrity governs stellate cell maintenance and behavior.
In normal adult liver, stellate cells preserve a quiescent state in their perivascular niche, the space of Disse. They receive systemic signals from distant organs via sympathetic nerves and the blood (‘sensing’). Stellate cells, in turn, release factors to maintain their surrounding microenvironment, thereby, contributing to liver homeostasis. During liver development and injury, hepatic stellate cells become activated and support neighboring cells to facilitate fetal hematopoiesis or tissue regeneration. Extracellular vesicles, soluble-factors, and cell-cell contacts are provided by stellate cells that could mediate supportive or immunosuppressive effects. Through the release of trophic factors also tumor cells might be attracted and supported as reported for MSCs in other organs. If the stem cell character of stellate cells cannot be maintained, cell differentiation into epithelial cell lineages such as hepatocytes can be induced to promote liver tissue reconstitution. If appropriate signals from their surrounding environment are missing, stellate cells sustain their activated state and deposit ECM proteins leading to fibrosis and cirrhosis. In chronic diseases associated with fibrosis/cirrhosis, the perivascular niche of stellate cells seems to be severely affected and may explain impaired liver regeneration and prevention of metastasizing tumor cell homing in liver sinusoids.
Cell-matrix and cell-cell contacts of stellate cells
The contact of cells via membrane-bound integrins, dystroglycan, syndecans and Lutheran blood group protein/basal cell adhesion molecule (Lu/BCAM) to other basement membrane proteins such as collagen 4 is mediated by laminins (Durbeej, 2010). The β1-integrin subunit (CD29) is frequently used to identify MSC populations (Semon et al., 2010) and is weakly present in quiescent stellate cells but becomes up-regulated at protein level during their activation. In addition to β1-integrin, Lu/BCAM, β3-integrin and β4-integrin are expressed by hepatic stellate cells (Carloni et al., 1996; Kubota et al., 2007; Rohn et al., 2018), which could mediate the effects of laminin-521 on stellate cell quiescence (Rohn et al., 2018).
In the liver, stellate cells can establish homotypic cadherin junctions with hepatocytes via N-cadherin (Kozyraki et al., 1996), which are important adhesion molecules in stem cell niches (Marthiens et al., 2010). Also signaling pathways such as notch signaling require a direct physical contact of signal-sending and signal-receiving cells. Notch1 receptor is expressed by bone marrow MSCs and hepatic stellate cells (Hiraoka et al., 2006; Sawitza et al., 2009; Schumacher et al., 2017) and was reported to be essential for the maintenance of neuronal stem cells in their niche and to suppress cell differentiation (Nyfeler et al., 2005; Basak et al., 2012; Shan et al., 2017). Conflicting reports are available for the notch 3 receptor, which seems to promote self-renewal and differentiation of stem cells (Edwards et al., 2017; Low et al., 2018; Sandel et al., 2018). In the liver, signal-sending cells that present notch ligands such as jagged1 (JAG1) are liver parenchymal cells and bile duct cells, whereas quiescent hepatic stellate cells exhibit no JAG1 protein synthesis (Jensen et al., 2004; Köhler et al., 2004; Sawitza et al., 2009). However, JAG1 appears together with notch3 during the activation of stellate cells (Sawitza et al., 2009; Schumacher et al., 2017). By providing JAG1 activated stellate cells can also support the development of neighboring cells. At present, the functional relevance of notch1 and notch3 signaling for stellate cells remains unclear. However, notch1 expression is mainly observed in freshly isolated stellate cells, indicating that notch1 could be involved in the maintenance of their quiescence state. In line with this, loss of notch1 or inhibition of notch signaling induces stellate cell activation and promotes angiogenesis (Banerjee et al., 2015).
Interactions between stellate and endothelial cells
Originally it was assumed that endothelial cells are only constituents of blood vessels, but many studies have shown that endothelial cells are also required for proper embryonal organ development and tissue regeneration (Lammert et al., 2001; Matsumoto et al., 2001; Ding et al., 2010; Hu et al., 2014; Rafii et al., 2016; Lorenz et al., 2018). In line with this, endothelial cells represent a basic element of the perivascular niche for MSCs. Indeed, endothelial cells of the bone marrow and liver sinusoids release C-X-C motif ligand 12 (CXCL12), also called stromal cell-derived factor 1 (SDF1) (Imai et al., 1999; Sawitza et al., 2009) (Figure 2C), which is the only ligand for the C-X-C motif receptor 4 (CXCR4). A CXCL12/CXCR4-dependent cell migration is known for MSCs from other organs (Wynn et al., 2004; Hong et al., 2009). Hepatic stellate cells express also CXCR4 and migrate to sinusoidal endothelial cells in response to CXCL12 (Sawitza et al., 2009). Moreover, stellate cells follow endothelial cells that invade the developing liver as demonstrated in the zebrafish (Danio rerio) (Yin et al., 2012). The expression of CXCL12 is not limited to endothelial cells in the liver. Also hepatic stellate cells start to release CXCL12 after their activation as described for other MSCs (Kubota et al., 2007; Hong et al., 2009; Sawitza et al., 2009). Through the CXCL12 secretion stellate cells may not only attract migrating stem/progenitor cells but also metastasizing tumor cells expressing CXCR4 (Correa et al., 2016). The interaction of CXCL12 and CXCR4 is an essential process to initiate and maintain stem cell niches, since the recruitment of stem cells from the bone marrow is partly mediated by local downregulation of CXCL12, which facilitates their mobilization from the bone marrow into the blood stream (Lapidot et al., 2005; Méndez-Ferrer et al., 2008).
As pericytes were shown to be important for angiogenesis and vessel maturation (Teichert et al., 2017) and endothelial cells release factors such as CXCL12, a mutual dependency between these cells can be expected. Indeed, hepatic stellate cells release vascular endothelial growths factors (VEGF), which maintain fenestration of sinusoidal endothelial cells (Ankoma-Sey et al., 2000; DeLeve et al., 2004), and angiopoietins (ANGPT1/2), which have been shown to promote the maturation of endothelial cells (Shimizu et al., 2005; Taura et al., 2008; Teichert et al., 2017). These findings indicate a tight relationship between stellate cells and sinusoidal endothelial cells in the liver that may stabilize the hepatic sinusoids and, thus, the perivascular niche in the space of Disse (Figure 2C).
Apart from CXCL12, other soluble factors such as WNT ligands can control the behavior of stellate cells, as β-catenin-dependent WNT (canonical) signaling maintains their quiescence (Kordes et al., 2008). Current knowledge points to endothelial cells of the central veins as a source for WNT ligands (WNT2 and WNT9b), which are involved in maintaining metabolic liver zonation (Leibing et al., 2018; Russell and Monga, 2018; Zhao et al., 2019). However, sinusoidal endothelial cells from normal and injured liver also express WNT2 (Klein et al., 2008; Ding et al., 2010), which can potentially contribute to sustain quiescence of stellate cells by canonical WNT signaling. This pathway can also preserve quiescence in hematopoietic stem cells and is essential to maintaining stemness (Reya et al., 2003; Sato et al., 2004; Fleming et al., 2008). However, non-canonical WNT pathways via the receptor frizzled 8 also seems to support hematopietic stem cells (Sugimura et al., 2012). Non-canonical WNT signaling can counteract canonical WNT signaling and may represent a regulatory mechanism involved in stabilizing hematopoietic stem cells in their niche. Further research is required to elucidate the WNT ligands that effectively control quiescence and activation of hepatic stellate cells.
During their activation, however, stellate cells significantly elevate the expression of non-canonical WNT ligands such as WNT4, WNT5a and WNT11 (Jiang et al., 2006; Kordes et al., 2008; Corbett et al., 2015). This ‘WNT switch’ can also be found in bone marrow MSCs (Davis and Zur Nieden, 2008). The relevance of an increased release of non-canonical WNT ligands is not yet clear but it can be assumed that non-canonical WNT ligands released by activated hepatic stellate cells influence the development of adjacent stem/progenitor cells as reported for the hematopoietic stem cell niche (Sugimura et al., 2012). Experimental evidence for this is provided by co-cultures of hepatic stellate cells with liver progenitor cells and hematopoietic stem cells (Wang et al., 2010); Kordes et al., 2013, 2015). This implies, that the stem cell niche character of the space of Disse should become apparent during fetal development, when the liver harbors hematopoietic stem/progenitor cells and supports blood formation before hematopoietic stem cells migrate into the bone marrow. In fact, GATA1-expressing myeloid progenitor cells are distributed throughout the liver parenchyma and are in close contact with desmin-positive stellate cells in the fetal rat liver (Kordes et al., 2013) (Figure 2F, G). The hematopoiesis in the fetal liver provides clear evidence for the existence of a stem cell niche in the space of Disse.
Innervation of the space of Disse
Humoral signals from different organs are carried via the blood stream to stem cell niches, but also the peripheral nervous system is involved in signal transmission. The egress of hematopoietic stem cells from the bone marrow into the blood is initiated by the sympathetic nervous system via innervation of MSCs (Katayama et al., 2006; Lucas et al., 2012). Norepinephrine release by the peripheral sympathetic nervous system triggers a decrease of CXCL12 and initiates hematopoietic stem cell mobilization (Katayama et al., 2006; Ferraro et al., 2011), which is enhanced by granulocyte colony-stimulating factor (G-CSF). Bone marrow MSCs synthesize G-CSF and are known to be associated with nerves (Haynesworth et al., 1996; Isern and Méndez-Ferrer, 2011). Nerve endings are also found in close contact to hepatic stellate cells. An α-adrenergic stimulation triggers Ca2+ transients, the release of myoinositol, RANTES, interleukin-8, and of prostaglandins and upregulate collagen and transforming growth factor expression in hepatic stellate cells (Häussinger et al., 1987; Athari et al., 1994; Reinehr et al. 1998; vom Dahl et al., 1999; McCuskey, 2004; Sancho-Bru et al., 2006; Sigala et al., 2013). Stellate cell-derived prostaglandins activate glycogenolysis in neighboring hepatocytes and, thereby, elevate local glucose concentration (Häussinger et al., 1987; Athari et al., 1994). Thus, stellate cells can integrate signals from sympathetic nervous system to influence the behavior of neighboring cells in their niche.
Alterations of the niche in the regenerating liver
In the injured liver, the composition of growth factors, cytokines and chemokines in the blood and tissue is altered and also cell-cell contacts are transiently lost when cells divide in order to restore liver mass. Changes in niche components of the regenerating or diseased liver can control the behavior of hepatic stellate cells. In normal liver, stellate cells remain quiescent and can contribute to liver homeostasis through the release of hepatocyte growth factor or in response to sympathetic nerve signals (Schirmacher et al., 1991; Ramadori et al., 1992; vom Dahl et al., 1999; Sumii et al., 2016). After partial hepatectomy, stellate cells first transiently loose cell-cell contacts with neighboring parenchymal cells and then deplete retinoid stores on the third day (Budny et al., 2007). Thereafter, activated stellate cells form clusters and intensify their cell contacts with parenchymal cells and finally increase their lipid stores again when tissue repair proceeds (Budny et al., 2007), showing that stellate cells strongly respond to changes in their microenvironment. This demonstrates that activated stellate cells can regain the quiescent state. After more severe liver injury, when the proliferative capacity of parenchymal cells is exhausted and LPC appear to reconstitute parenchymal cells and cholangiocytes through differentiation, stellate cells can also support the differentiation of LPC as demonstrated by co-culture experiments (Wang et al., 2010) (Figure 3). However, stellate cells themselves can acquire a LPC-phenotype and differentiate into hepatocytes and cholangiocytes (Kordes et al., 2014) (Figure 3). To ensure their supportive effects and developmental potential, stellate cells can survive even under adverse environmental conditions. Despite expression of CD95/Fas in quiescent hepatic stellate cells, these cells are resistant towards CD95 ligand-induced apoptosis (Reinehr et al., 2008; Sommerfeld et al., 2009). Here, CD95 ligand triggers an inactivating tyrosine nitration of CD95/Fas and simultaneously stimulates stellate cell proliferation through shedding of epidermal growth factor (EGF) followed by autocrine EGF receptor activation (Reinehr et al., 2008).
Hedgehog (HH) signaling is important for liver development and regeneration but in the uninjured adult liver HH signaling is silenced and only few cells around portal tracts exhibit an active HH pathway (Sicklick et al., 2006; Gao et al., 2018). Therefore, HH signaling seems to be dispensable for the stellate cell niche in the normal liver. In line with this, quiescent hepatic stellate cells express the inhibitory HH-interacting protein, which is down-regulated after their activation in culture (Choi et al., 2009). However, evidence has been presented that HH signaling determines stem cell development in their niche (Brownell et al., 2011). After liver injury, hepatocytes release the HH ligands sonic hedgehog (SHH) and indian hedgehog (IHH) that can activate the HH pathway in neighboring stellate cells and LPC, thereby promoting cell viability and growth (Sicklick et al., 2005, 2006). Thus, HH ligands alter the niche environment of stellate cells, triggers their activation, and may influences their development as observed for bone marrow MSCs (Spinella-Jaegle et al., 2001).
The stellate cell niche in liver diseases
In chronic liver diseases, activated stellate cells lose their beneficial effects on tissue regeneration, are misguided and deposit collagens, thereby, contributing to fibrosis (Friedman et al., 1985). The situation, however, is more complex than previously anticipated, as other cells such as portal and bone marrow-derived myofibroblasts as well as mesenchymal cells that originate from epithelial cells via epithelial-to-mesenchymal transition (EMT) were also described to be involved in fibrogenesis (Forbes et al., 2004; Russo et al., 2006; Beaussier et al., 2007; Kalluri and Weinberg, 2009). Chronic inflammation usually precedes fibrosis, which is associated with long-lasting alterations of niche components such as ECM composition in the space of Disse. Under these conditions regenerative processes through resident epithelial cells, stellate cells and other MSCs of the body are obviously impaired but can be restored to a certain extent by transplantation of allogenic MSCs (Zhao et al., 2005; Oyagi et al., 2006). Although transplanted MSCs are capable of ameliorating liver fibrosis, evidence has accumulated that MSCs contribute to fibrosis in many organs such as muscle, lung, heart and liver (Marriott et al., 2014; Kramann et al., 2015; Liu et al., 2015; Ieronimakis et al., 2016; Trial et al., 2016). Thus, whether MSCs are fibrotic or fibrolytic seems to be context-dependent and to be controlled by environmental cues. An age-related decline in stem cell niche integrity is known (Mayack et al., 2010; Maryanovich et al., 2018) and most likely responsible for these differential effects. The accumulation of somatic DNA damage and oxidative stress are major triggers of cell aging. Stem cell senescence, apoptosis, and differentiation can lead to successive stem cell depletion and impair the regenerative capacity of aged tissues. DNA damage of melanocyte stem cells for instance can trigger their differentiation into melanocytes within the hair follicle, thereby decreasing the melanocyte stem cell pool, which can ultimately lead to graying of hair (Inomota et al., 2009). Age-related impairment of osteogenic differentiation of bone marrow MSCs is due to effects of oxidative stress on HH signaling (Kim et al., 2010). Chronic inflammation can elicit enhanced telomere shortening and defects in DNA repair mechanisms, which lead to DNA damage in adult stem cells (Mimeault and Batra, 2009) and could be one reason that causes niche alterations in chronic liver disease. An altered perivascular niche in chronic inflammation may be involved in dysregulation of MSCs and their contribution to fibrosis.
Niches formed by activated stellate cells can also have adverse effects through supporting cancer stem cells and promotion of tumor cell progression as observed in hepatocellular carcinoma (Amann et al., 2009; Knaak et al., 2018; Wen et al., 2019). Hepatic stellate cells can further enable the engraftment of metastasizing melanoma cells in liver sinusoids via a CD146-dependent mechanism (Correa et al., 2016). Immunosuppressive functions, which can contribute to tumor cell survival, are consistently reported for stellate cells and bone marrow MSCs (McIntosh and Bartholomew, 2000; Krampera et al., 2003; Lee et al., 2005; Chen et al., 2006; Schildberg et al., 2011). Stellate cell engagement in niche formation may critically depend on their activation, as non-activated stellate cells seem to support the quiescence-associated phenotype of pancreatic ductal adenocarcinoma cells via interleukin-8 release while this positive effect is lost when stellate cells activate and become myofibroblasts as investigated in vitro (Lenk et al., 2017). The stem cell-friendly microenvironment in the space of Disse and the provision of niche elements by activated stellate cells in conjunction with their immunosuppressive functions could be the reason for the frequent homing of migrating tumor cells in the liver, predisposing this organ for metastasis. Alterations of this perivascular niche in chronic diseases may explain impaired homing of intrahepatic metastasis in liver cirrhosis (Ruebner et al., 1961).
Conclusions
The finding that stellate cells represent liver-resident MSCs allows for explanations of seemingly discrepant observations regarding ECM deposition and hepatic stellate cell function as MSCs made in the past. Stellate cells can, on the one hand, be seen as triggers of liver fibrosis and on the other hand, MSC transplantation can ameliorate liver fibrosis in experimental settings. We postulate that the niche integrity determines whether stellate cells/MSCs have pro- or antifibrotic properties. Moreover, this concept may enable new therapeutic approaches for the treatment of chronic liver disease. Further aspects are offered by the potential of stellate cells to acquire a quiescent state in their niche, to influence neighboring cells by immunomodulatory and trophic factors, and to differentiate. First attempts are made to enforce differentiation of stellate cell-derived myofibroblasts in fibrotic liver of mice into hepatocytes by overexpression of defined hepatic transcription factors (Rezvani et al., 2016; Song et al., 2016). Identification of perivascular niche components that are lost in chronic liver diseases and reestablishment of these factors may not only offer new therapeutic approaches to treat patients with liver fibrosis but also new aspects on the aging liver.
Acknowledgements
The authors are grateful to the German Research Foundation (Deutsche Forschungs-gemeinschaft, DFG) for supporting this work through the Collaborative Research Center SFB 974 ‘Communication and System Relevance during Liver Injury and Regeneration’ (Funder Id: http://dx.doi.org/10.13039/501100001659, project number 190586431).
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