The influence of tissue spatial geometry and functional organisation on liver regeneration

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Abstract

The adult liver exerts crucial functions, including nutrient metabolism and storage, bile production and drug detoxification. These complex functions expose the liver to constant damage induced by toxins, metabolic intermediates and oxidative stress. However, the adult liver exhibits an exceptional regenerative potential, which allows fast and efficient restoration of tissue architecture and function both after tissue resection and toxic damage. To accomplish its vital role, the liver shows a peculiar tissue architecture into functional units, which follow the gradient of oxygen and nutrients within the parenchyma. Much less is known about the influence of tissue spatial geometry and functional organisation on adult liver regeneration. Here I examine the experimental evidence in mouse models showing that the spatial organisation of the epithelial and mesenchymal compartments plays a key role in liver regeneration and favours the establishment of regenerative adult liver progenitors following liver injury. I also discuss the advantages and limitations of human and mouse 3D hepatic organoid systems, which recapitulate key aspects of liver function and architecture, as models of liver regeneration and disease. Finally, I analyse the role of the YAP/TAZ transcriptional co-activators as a central hub sensing the extra-cellular matrix (ECM), metabolic and epigenetic remodelling that regulate liver regeneration and promote liver disease, such as fibrosis, chronic liver disease and liver cancer. Together, the findings summarised here demonstrate that local physical and functional cellular interactions determined by the liver peculiar spatial geometry, play a crucial role in liver regeneration, and that their alterations have important implications for human liver disease.

Introduction

The adult liver is the largest internal organ of the body and exerts crucial functions, including nutrient metabolism and storage, regulation of blood glucose levels, synthesis of plasma proteins, bile production and drug detoxification. To achieve these key functions, the adult liver has peculiar tissue structure and geometry, which allow efficient nutrient and oxygen distribution across the liver parenchyma [1], [2], [3]. Nutrients are supplied by the portal vein, which connects the liver to the gastrointestinal tract. Oxygenated blood is supplied by the hepatic artery. Biliary ducts collect the bile and export it to the duodenum for digestive purposes. Portal vein, hepatic artery and biliary ducts form the so-called portal triad. The central vein returns poorly oxygenated and metabolite-rich blood to the systemic circulation. Thus, oxygen and nutrient-rich blood flow from the portal triad to the central vein, creating a gradient of oxygen and nutrients within the liver parenchyma, whereas the bile flows in the opposite direction. The spatial distribution of the central vein and portal triad defines the liver tissue spatial and functional organisation [1] (Fig. 1). The basic histological unit of the liver is the lobule, which has a hexagonal shape, with the central vein in the middle and portal triads located at each corner. The minimal functional unit of the liver is the acinus. The acinus has an irregular shape, which results from the intersection of two adjacent lobules and is aligned around the veins. The acinus is centred around the portal triad and is divided into three zones, which follow the decreasing gradient of nutrient and oxygen from the portal triad (zone 1) to the central vein (zone 3) [1]. At the cellular level, the adult liver is composed of two epithelial cell types, hepatocytes (~60% of total liver cells) and cholangiocytes (3–5%), mesenchymal cells, including hepatic stellate cells (HSCs) (~8%), resident macrophages, called Kupffer cells (~15%), and endothelial cells (15–20%) [1], [2], [3] (Fig. 1).

Due to its key function, the adult liver is constantly exposed to damage caused by toxins, oxidative stress and intermediate metabolites. Importantly, the adult liver exhibits excellent regenerative potential both after resection of 70% of its mass (also known as partial hepatectomy) and following toxic damage [4]. This is even more remarkable considering that the adult liver is a slowly self-renewing organ and lacks an evident stem-cell compartment in homeostasis, opposite to other highly regenerative organs such as intestine, stomach and skin. Thus, cellular plasticity awakens liver cells in response to damage and induces cell-fate changes, such as cell trans-differentiation and de-differentiation into progenitors, to achieve efficient liver regeneration [5], [6], [7], [8]. However, persistent liver injury, caused by alcohol abuse, metabolic dysfunctions, severe obesity and viral infections, overwhelms liver regenerative capacity and impairs liver function, causing chronic liver disease and predisposing to liver cancer [9].

Liver organoid systems have recently emerged as reliable models of liver regeneration and disease [10]. Here organoid systems are defined as 3D self-organising structures, which recapitulate aspects of the native tissue architecture and function, in agreement with the guidelines established by the hepatic, pancreatic and biliary (HPB) Organoid Consortium [10].

Increasing evidence indicates that the spatial geometry and tissue architecture not only allows the efficient accomplishment of liver function, but also influences liver regenerative capacity in response to tissue resection and toxic damage. In this review, I examine the experimental evidence showing the influence of adult liver epithelial and mesenchymal spatial organisation in liver injury-response and regeneration in mouse models. In addition, I discuss the advantages and limitations of 3D hepatic organoids to recapitulate liver tissue geometry and model liver regeneration and disease. Finally, I examine the implications of ECM deposition and fibrosis, and the central role of the YAP/TAZ-mediated signalling, in adult liver regeneration mediated by adult liver progenitors and human liver disease, such as fibrosis, chronic liver disease and liver cancer.

Hepatocytes represent ~60% of total liver cells and play a major role in liver regeneration [11], [12], [13]. They are crucial for nutrient metabolism and storage, exert detoxification functions, and produce the bile. Hepatocytes have specialised metabolic and drug detoxification competence according to their location in proximity to either the central or the portal vein. This so called zonation is consistent with the gradient of oxygen and nutrients within the lobule [1]. Hepatocytes show a multipolar organisation, which is dependent on ECM interactions, cell-cell adhesion and cytoskeleton architecture [14], [15]. The apical domain defines contiguous lumina, which form a network of bile canaliculi that converge into biliary ducts. On their basal side, hepatocytes face the sinusoids, which are fenestrated capillaries showing a discontinuous endothelium to allow the exchange of nutrients and metabolites with the bloodstream. This is facilitated by the absence of a dense basal lamina [14], [15]. Sinusoids influence the orientation of division of the hepatocytes [16]. Alterations of the mechanical homeostasis determined by the blood flow in sinusoids play an important role in liver regeneration [17].

Partial hepatectomy leads to a coordinated cellular response and significant restoration of liver size and function within weeks [4]. This enables to maintain a constant liver to body weight ratio, which is crucial for adult body homeostasis, a concept called hepatostat [11]. Being the most abundant cell type, the hepatocytes play a central role in the liver response to partial hepatectomy. Of note, after partial hepatectomy, the overall liver shape changes, thus indicating that the liver prioritises the replacement of its functional units over the restoration of its correct shape. The change in liver shape is due to a compensatory hypertrophy of the hepatocytes in the remnant liver, followed by a proliferation wave from the periportal to the pericentral area of the lobule [18]. This gradient of proliferation ensures restoration of the tissue mass while maintaining liver functionality, since proliferation is associated with reduced expression of functional hepatocyte genes [4]. Proliferation is also accompanied by the transient re-acquisition of chromatin and transcriptional profiles of foetal progenitors [19] and early postnatal hepatocytes [20]. This is consistent with the fact that adult hepatocytes can de-differentiate into bipotent liver progenitors after toxic damage [21], [22], [23], as they are capable to give rise to both hepatocytes and cholangiocytes, resembling the liver epithelial embryonic progenitors, the hepatoblasts [2], [3], [24].

Although being slowly self-renewing in homeostasis, increasing evidence demonstrates that the majority of the hepatocytes can acquire proliferation in response to hepatectomy and toxic damage [25], [26], [27]. The nature of the injury determines the activation of the hepatocytes located in proximity to the injury source. Different regional markers defining hepatocytes subpopulations involved in homeostasis, damage-response and regeneration have been identified. Periportal hepatocytes express the classic cholangiocyte marker Sox9 [28]; pericentral hepatocytes express the WNT-related stem-cell marker Axin2 [29]; TERT+ hepatocytes are present throughout the liver parenchyma and in zonal boundaries [30]. Are all hepatocytes equally competent to proliferate and regenerate the liver? Recent findings highlight midlobular/zone 2 hepatocytes as the most proliferative hepatocyte population [20], [25], [31], [32]. Fate-mapping of 14 different hepatocyte populations in the mouse liver revealed that midlobular/zone 2 hepatocytes are the main proliferative hepatocyte population in homeostasis [31]. EdU labelling showed that midlobular/zone 2 hepatocytes exhibit higher proliferation potential in response to partial hepatectomy [20]. Midlobular/zone 2 hepatocytes also contribute to liver regeneration both after periportal injury induced by the 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC) diet, which damages zone 1 hepatocytes, and pericentral injury induced by Carbon tetrachloride (CCl4), which damages zone 3 hepatocytes [31]. A genetic strategy called ProTracer, which allows continuous recording of in vivo cell proliferation, confirmed that midlobular/zone 2 hepatocytes exhibit more proliferation in both the homeostatic and damaged liver [32]. Why should the liver favour the response of the hepatocytes in midlobular/zone 2 over zone 1 and zone 3? Being further away from both the central (zone 3) and the portal vein (zone 1), where liver damage occurs, zone 2 is less susceptible to damage. Thus, midlobular hepatocytes appear to be a reservoir of proliferating hepatocytes protected from liver damage [31], [32]. In addition, the increased proliferation capacity of midlobular/zone 2 hepatocytes may be a way to preserve liver metabolic functions, which are exerted predominantly by hepatocytes in zone 1 and 3. Supporting this, i) single-cell RNA-sequencing showed that periportal/zone 1 and pericentral/zone 3 hepatocytes maintain their metabolic competence, while midlobular/zone 2 hepatocytes proliferate after partial hepatectomy [20]; ii) ATAC-sequencing combined with RNA-sequencing showed that, after partial hepatectomy, a subset of hepatocytes retain chromatin accessibility and expression of genes involved in metabolic functions [19]. Together, this suggests that the peculiar spatial organisation allows the liver to preserve its vital metabolic functions in response to both tissue resection and toxic damage. Notably, all the different experimental approaches that highlighted the important role of midlobular hepatocytes, revealed also high regional hepatocyte proliferation after damage. Therefore, this confirms that the majority of the hepatocytes can acquire proliferation and that the spatial location within the liver lobule determines the activation of specific hepatocyte subpopulations according to the type of injury. The next challenge will be to determine the role of regional metabolic inputs and hepatocyte competence in the regulation of the epigenetic and transcriptional mechanisms that promote liver regeneration after damage [8].

Is hepatocyte spatial organisation and geometry recapitulated in 3D organoid systems? Hepatocyte organoids can be derived from mouse liver tissue [33], [34], human primary hepatocytes and foetal liver cells isolated from human embryos of 11–20 weeks of gestation [33]. Adult hepatocyte organoids have the potential to engraft into the damaged mouse liver and exhibit structured bile canaliculi and functional hepatocyte features [33], [34]. In culture conditions promoting organoid expansion, hepatocyte organoids resemble the transcriptional profiles of the regenerative hepatocytes observed after partial hepatectomy and exhibit increased expression of pericentral hepatocytes markers [33], [34]. However, change in culture conditions can induce the expression of periportal hepatocyte markers [34] and trans-differentiation into cholangiocytes [33], indicating that hepatocyte organoids exhibit high plasticity. Hepatocytes derived upon differentiation of human induced-pluripotent stem cells (iPSCs) can be grown together with endothelial and mesenchymal cells to form 3D structures resembling the liver bud, which become vascularised after transplantation in mouse [35], [36]. iPSC-based methods also allow concomitant growth and specification of different liver cell types. Human iPSC-derived epithelial organoids, which contain both hepatocytes and cholangiocytes, have been used as a model of hepatic steatosis [37]. Human iPSC-derived multi-tissue organoids contain multiple stromal and epithelial liver cell types, including hepatocytes and cholangiocytes, Kupffer cells and HSCs. They allow modelling steatosis, inflammation and fibrosis observed in non-alcoholic steatohepatitis [38], and drug-induced cholestatic injury and mitochondrial toxicity [39]. Interestingly, human multi-tissue organoids established directly from iPSC differentiation show increased expression of periportal hepatocyte makers [38], whereas organoids established from iPSC-derived foregut progenitors show a similar amount of periportal and pericentral hepatocytes [39].

Together, these findings highlight adult and iPSC-derived hepatic organoids as models of hepatocyte-mediated liver regeneration and human liver disease. These organoid systems recapitulate, at least in part, mature hepatocyte functional properties and the complexity of the bile canaliculi. The next important challenge will be the identification of the culture conditions allowing recapitulating in vitro the hepatocyte zonation in the liver lobule.

Cholangiocytes modify and collect the bile produced by the hepatocytes into biliary ducts, which are one of the defining elements of the portal triad. Intrahepatic biliary ducts converge into the common bile duct, which then exports the bile to the duodenum for digestive purposes [40], [41]. Biliary ducts can be classified into small ductules (<15 µm) and large ducts according to their diameter [41]. Biliary ductules are formed by small cholangiocytes, which are cuboidal in shape and characterised by tight junctions between cells and microvilli facing the lumen. Large cholangiocytes mostly define interlobular and extrahepatic ducts, are columnar in shape and have a primary cilium [41]. Heterogeneity in size and shape influences cholangiocyte regenerative capacity: large cholangiocytes exhibit higher proliferation in response to certain types of injury (e.g. bile acids, surgical ligation of the common bile duct and CCl4); small cholangiocytes exhibit higher plasticity, being capable of restoring both small and large biliary ducts after injury [42]. Lineage-tracing experiments in response to damage induced by thioacetamide (TAA) showed that proliferative cholangiocytes are mainly located in the peripheral ductules [43]. Of note, heterogeneity was observed even within the peripheral compartment, since not all ductules exhibited proliferation, and the proliferative ductules gave rise to both small and large clusters, which is indicative of different rounds of cell division [43]. Senescent cholangiocytes can induce paracrine senescence in the surrounding periportal hepatocytes via TGF-β dependent mechanisms, and compromise liver regenerative capacity after both periportal damage induced by DDC and partial hepatectomy [44]. Underlying the relevance of this paracrine mechanism, periportal hepatocytes exhibit senescence in human liver biopsies from patients with primary sclerosing cholangitis and primary biliary cholangitis [44].

Toxic injury induces biliary proliferation and expansion of biliary ducts in both mouse and human liver, a phenomenon called ductular reaction [45]. These expanding ductal branches are associated with the establishment of bipotent liver progenitors capable of regenerating the epithelial compartment after damage [6], [8], [46]. Both adult liver epithelial cell types can de-differentiate into bipotent liver progenitors, consistent with the developmental origin of both hepatocytes and intrahepatic cholangiocytes from a common embryonic progenitor, the hepatoblast [2], [3], [24]. These adult bipotent liver progenitors originate predominantly in a specific location of the liver lobule, the canal of Hering, which is the finest ramification of the biliary tree, connecting the bile canaliculi and large intrahepatic and extrahepatic biliary ducts [47]. Therefore, this suggests that the canal of Hering provides a favourable environment to acquire a bipotent progenitor state. Whether this is due to specific signalling molecules and cytokines or to enriched hepatocyte-cholangiocyte cell interactions in this area of the liver lobule, remains unknown. Adult liver progenitors acquire a specific molecular signature, including the expression of TROP2 [48], [107], and can infiltrate the parenchyma to repair the epithelial architecture [46]. How adult liver progenitors sense the damage, and how their migration patterns within the parenchyma influence liver regeneration, is unclear. This progenitor response to injury is crucial for liver regeneration when the hepatocytes are compromised (e.g. chronic injury, over-expression of p21, deletion of Mdm2, β1 integrin or β-catenin) [49], [50], [51], [52], [108]. In this scenario, lineage-tracing experiments in mouse models demonstrated that intrahepatic cholangiocytes act as facultative liver progenitors, which restore up to 70% of total hepatocytes [49], [50], [51], [52]. Are all cholangiocytes capable to acquire a bipotent progenitor state? Our data indicated that ~15% of adult mature cholangiocytes isolated from the mouse healthy liver can acquire a bipotent progenitor state when grown as organoid cultures [53]. Supporting a degree of heterogeneity within cholangiocytes, ~25% of cholangiocytes show high activity of the YAP/TAZ signalling in the liver [54], which is required for cholangioyte regenerative properties [54], [55]. However, increased YAP/TAZ levels do not appear to be an intrinsic feature of a distinct cholangiocyte progenitor-like subpopulation in the homeostatic liver; on the contrary, YAP/TAZ levels become dynamically up-regulated in response to bile acid-induced injury [54], consistent with the function of the cholangiocytes to collect and modify the bile. Supporting a dynamic regulation of the cholangiocyte progenitor state, we found that transient epigenetic remodelling, occuring at early stages after liver damage in vivo, sustains the activity of the YAP/TAZ signalling and is required for the expression of stem-cell genes to drive the de-differentiation of mature cholangiocytes into bipotent liver progenitors [53].

Together, these findings indicate that cholangiocytes exhibit high plasticity in response to injury, which is required to regenerate the biliary tree and restore the damaged liver epithelia when the hepatocytes are compromised. Further characterisation of the mechanisms regulating cholangiocyte heterogeneity and plasticity will have important implications for regenerative medicine to repair the vast hepatocyte necrosis and senescence detected in chronic liver disease [56] and for treatment of liver cancer, where prominent progenitor features are associated with a poor prognosis [57].

Cholangiocyte organoids can be derived from human and mouse adult liver tissue biopsies. They can be derived from intrahepatic [58], [59] and extrahepatic [60], [61] biliary ducts, and the gallbladder [62] or from iPSCs [63], [64]. Adult cholangiocyte organoids are self-renewing cultures, named intrahepatic (ICOs), extrahepatic (ECOs) and gallbladder (GCOs) cholangiocyte organoids according to the cell of origin [10]. ICOs express stem-cell genes defining bipotent adult liver progenitors in vivo (e.g. Trop2) [53], [58], [59] and recapitulate the transcriptional and epigenetic profiles of regenerative cholangiocytes in the mouse injured liver in vivo [53]. Consistent with their resemblance of bipotent liver progenitors, ICOs can differentiate into functional hepatocytes in vitro and upon transplantation in vivo, showing engraftment potential in the damaged mouse liver, although with low efficiency [58], [59]. Confirming their high plasticity, adult cholangiocyte organoids derived from one region of the biliary tree can repair different regions of the biliary tree after transplantation in vivo [65]. Remarkably, upon transplantation into the intrahepatic biliary tree of human donor livers showing ischaemic duct injury, human GCOs were shown to regenerate 40% to 85% of the injected human biliary ducts [65]. Of note, GCOs did not form hepatocytes upon transplantation in human donor livers [65], thus suggesting that either these experimental conditions specifically promoted the restoration of the damaged biliary tree or that differentiation into hepatocytes is a unique property of intrahepatic cholangiocytes. The latter is in line with the common developmental origin of intrahepatic cholangiocytes and hepatocytes from the hepatoblasts, whereas extrahepatic cholangiocytes have a common developmental origin with the pancreas and duodenum [2], [3], [24].

Together, these findings show that cholangiocyte organoids retain the cholangiocyte plasticity observed during liver regeneration, and are promising systems for regenerative medicine, taking advantage of their long-term expansion in vitro and their capacity of engraftment in the damaged liver in vivo.

Section snippets

The mesenchymal compartment and ECM deposition in liver regeneration and disease

Resident liver mesenchymal cells can stimulate the response to injury mediated by liver progenitors, via secretion of growth factors [4], [7]. For example, after periportal damage induced by DDC, mesenchymal Fgf7 promotes the activation of liver progenitors [66], [67] and secretion of the Notch-ligand Jagged 1 promotes differentiation of the progenitors to restore biliary ducts [68]. In addition, mesenchymal cells regulate the proliferation capacity of adult liver progenitors via direct cell

The YAP/TAZ signalling in liver regeneration and disease

How do ECM remodelling and increased stiffness in the damaged liver influence the epithelial cells at the molecular level? Increased tissue stiffness induces nuclear translocation of the transcriptional co-activators YAP and TAZ, which are key mediators of mechanotransduction [87]. The interplay between ECM and YAP/TAZ is bidirectional, since YAP expression is induced in both HSCs [88] and hepatocytes [86] after liver injury, promoting collagen deposition and liver fibrosis. Additional inputs

Conclusions

Liver tissue geometry and functional organisation is determined by the direction of the blood flow, from the portal triad to the central vein, generating a gradient of oxygen and nutrients within the liver lobule. The recent development of single-cell transcriptomics, combined with lineage-tracing in mouse models, have allowed the identification of subpopulations of epithelial and mesenchymal cells that show distinct molecular signatures according to their spatial location in the liver lobule (

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by MRC core funding to the MRC Laboratory for Molecular Cell Biology at University College London, award code (MC_U12266B). LA thanks the members of the laboratory for helpful discussions. LA apologises to all the authors whose work could not be cited due to space limitations. The graphical abstract and the figures were created with Biorender.com.

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