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Schematic histological structure of liver tissue. Functional units of liver tissue are formed by trabeculae and accompanying blood sinusoids. Liver tissue gets its afferent blood supply from two sources: hepatic artery and portal vein. Hepatic arterioles (HAs) and the terminal branches of portal vein (PV) merge to form blood sinusoids (BSs) lined with endotheliocytes and drained into the central veins (CVs). In the sinusoids, close to endothelium reside liver macrophages named Kupffer cells. Bile produced by hepatocytes flows in the opposite direction and is discharged into the bile ducts (BDs). Hepatic arterioles, terminal branches of portal vein, and the smallest bile ducts are drawn together forming compact structures called portal tracts shown at the right side of the figure. Liver trabeculae are built of hepatocytes. The inner cavities of trabeculae form canaliculi which are closed at the central ends of the lobules (left side of figure) and while on their way to BD they convert into bile ductules (BDLs) via a transitory zone called the canals of Hering (CH). Bile ductules drained into the bile ducts are lined with cholangiocytes, and the canals of Hering contain LSPCs. Tiny spaces between trabeculae and the endothelium of blood sinusoids are called the spaces of Disse (SD). They participate in the bidirectional traffic of different substances between blood and hepatocytes and contain stellate (Ito) cells.
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The emerging field of regenerative medicine offers innovative methods of cell therapy and tissue/organ engineering as a novel approach to liver disease treatment. The ultimate scientific foundation of both cell therapy of liver diseases and liver tissue and organ engineering is delivered by the in-depth studies of the cellular and molecular mechani...
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Mesenchymal stem cells (MSCs) possess huge potential for regenerative medicine. For tissue engineering approaches, scaffolds and hydrogels are routinely used as extracellular matrix (ECM) carriers. The present study investigated the feasibility of using textile-reinforced hydrogels with adjustable porosity and elasticity as a versatile platform for...
Citations
... These lobules consist of large polygonal hepatocytes stacked on top of each other and demarcated by fibrous septa containing variable amounts of connective tissue. These hepatocytes are estimated to be approximately 80 % of the liver tissue, while other nonparenchymal cells represent 20 % [50,51]. The portal triad consists of hepatic artery, portal vein, and bile duct and surrounded by loose connective tissue. ...
Liver transplantation represents the only definitive treatment for patients with end-stage liver disease. However, the shortage of liver donors provokes a dramatic gap between available grafts and patients on the waiting list. Whole liver bioengineering, an emerging field of tissue engineering, holds great potential to overcome this gap. This approach involves two main steps; the first is liver decellularization and the second is recellularization. Liver decellularization aims to remove cellular and nuclear materials from the organ, leaving behind extracellular matrices containing different structural proteins and growth factors while retaining both the vascular and biliary networks. Recellularization involves repopulating the decellularized liver with appropriate cells, theoretically from the recipient patient, to reconstruct the parenchyma, vascular tree, and biliary network. The aim of this review is to identify the major advances in decellularization and recellularization strategies and investigate obstacles for the clinical application of bioengineered liver, including immunogenicity of the designed liver extracellular matrices, the need for standardization of scaffold fabrication techniques, selection of suitable cell sources for parenchymal repopulation, vascular, and biliary tree reconstruction. In vivo transplantation models are also summarized for evaluating the functionality of bioengineered livers. Finally, the regulatory measures and future directions for confirming the safety and efficacy of bioengineered liver are also discussed. Addressing these challenges in whole liver bioengineering may offer new solutions to meet the demand for liver transplantation and improve patient outcomes.
... Though there are varied therapeutic strategies, one of the best options for treatment in terminal liver infections is liver transplantation. This in itself is limited by restricted organ supply, the complexity of human leukocyte antigen (HLA) matching, immunologic side effects, and financial constraints [1]. Moreover, long-term survival with this option is not guaranteed. ...
Hepatitis B and C viruses (HBV and HCV) are the leading causes of end-stage liver disease worldwide. Although there is a potent vaccine against HBV, many new infections are recorded annually, especially in poorly resourced places which have lax vaccination policies. Again, as HBV has no cure and chronic infection is lifelong, vaccines cannot help those already infected. Studies to thoroughly understand the HBV biology and pathogenesis are limited, leaving much yet to be understood about the genomic features and their role in establishing and maintaining infection. The current knowledge of the impact on disease progression and response to treatment, especially in hyperendemic regions, is inadequate. This calls for in-depth studies on viral biology, mainly for the purposes of coming up with better management strategies for infected people and more effective preventative measures for others. This information could also point us in the direction of a cure. Here, we discuss the progress made in understanding the genomic basis of viral activities leading to the complex interplay of the virus and the host, which determines the outcome of HBV infection as well as the impact of coinfections.
... Following a sublethal injury, the human liver can undergo compensatory hypertrophy, characterized by the enlargement of hepatocytes, followed by hyperplasia. This intrinsic regenerative ability enables the restoration of parenchymal tissue [5][6][7]. This phenomenon has formed the basis of conservative management of acute liver failure, major liver resection for tumors, and living donor liver transplantation. ...
... Nevertheless, the patient needs significant support (when a considerable mass needs to be resected) for multiple functions during this period of regeneration as the liver is the body's metabolic powerhouse. In a distinct context, chronic liver injury results from varied etiologies, the Extracellular Matrix (ECM) of the liver itself has been disrupted because of the excessive deposition of ECM proteins [7]. Such cirrhotic livers which are accompanied by fibrosis also require an ECM remodeling to support liver regeneration or wound healing [8]. ...
Liver transplantation is the only optimal method used for treating end-stage liver disease, originated in 1957 and was developed as a mainstream methodology over a span of two decades. Nevertheless, this procedure remains in a state of perpetual evolution, marked by ongoing advancements and adaptations. Moreover, the field of liver transplantation is still baffled by the non-availability of donor livers. Numerous scientific and technical innovations, both direct and tangential to liver transplantation, have emerged, contributing to its refinement, and augmenting the overall progress in this intricate domain.
... The liver clock mechanism is largely affected by changes in the SCN [33]. In addition, the liver is a relatively homogeneous peripheral organ, with most of its constituent cells being hepatic parenchymal cells [34]. Therefore, in many studies, the SCN is used as the central clock and the liver as the peripheral clock as the index for evaluation [5,35,36]. ...
Prostaglandins are bioactive compounds, and the activation of their receptors affects the expression of clock genes. However, the prostaglandin F receptor (Ptgfr) has no known relationship with biological rhythms. Here, we first measured the locomotor period lengths of Ptgfr-KO (B6.129-Ptgfrtm1Sna) mice and found that they were longer under constant dark conditions (DD) than those of wild-type (C57BL/6J) mice. We then investigated the clock gene patterns within the suprachiasmatic nucleus in Ptgfr-KO mice under DD and observed a decrease in the expression of the clock gene cryptochrome 1 (Cry1), which is related to the circadian cycle. Moreover, the expression of Cry1, Cry2, and Period2 (Per2) mRNA were significantly altered in the mouse liver in Ptgfr-KO mice under DD. In the wild-type mouse, the plasma prostaglandin F2α (PGF2α) levels showed a circadian rhythm under a 12 h cycle of light–dark conditions. In addition, in vitro experiments showed that the addition of PTGFR agonists altered the amplitude of Per2::luc activity, and this alteration differed with the timing of the agonist addition. These results lead us to hypothesize that the plasma rhythm of PGF2α is important for driving clock genes, thus suggesting the involvement of PGF2α- and Ptgfr-targeting drugs in the biological clock cycle.
... The blood in the portal vein and hepatic artery of the portal triad flows to the liver sinusoids and finally to the central vein [24]. Hepatocytes as major functional cells in the liver compromised more than 60-70% of liver cells [25]. These parenchymal cells interact with other hepatocytes in apical surfaces to make bile canaliculi structures for collecting the secreted bile [26,27]. ...
... This layered structure can be produced with triple cell types (sandwich culture) [15,25]. In the sandwich cell culture, the hepatocyte cell layer was overlaid with/without adding ECM, with EC or HSC (on top or down) [46]. ...
Primary hepatocytes as liver stem cells can proliferate under liver injury. Hepatocytes are the major parenchymal cells (PC) in the liver and play an important role in liver metabolism. Hepatocytes are considered as a gold standard tool for drug toxicity/screening or liver disease modeling. Though the maturation and functions of hepatocytes are lost under routine 2-dimensional (2D) culture conditions. Recent studies revealed that interactions of hepatocytes with non-parenchyma cells (NPC) under 3D culture conditions can be an alternative option to overcome these problems. Co-culture of hepatocytes with NPC facilitated in-vitro liver disease models such as fibrosis, steatosis and non-alcoholic fatty liver disease (NAFLD), cholestasis, and viral hepatitis. This review described the co-culture of liver PC with NPC under 2D and 3D culture systems.
... Studies involving rats, patients, and fish Danio rerio showed that hepatocytes and cholangiocytes can play a role of progenitor cells by passing through the dedifferentiation stage followed by differentiation into other types of cells necessary to restore lost functions [3]. There is evidence that regeneration involves not only resident cells, but bone marrow and hepatic stellate cells (Ito cells) [4]. Endothelial bone marrow progenitor cells participate in the regeneration of the hepatic endothelium, and the capability of mesenchymal stem cells (MSC) for the multilinear differentiation suggests their possible participation in the regeneration of liver parenchyma [5]. ...
On day 1 post 30% and 70% hepatectomy, the hepatic regenerative processes have been studied in 3-month-old (young) and 9-month-old (old) male Wistar rats. Regardless of the resected liver volume, old rats were found to have more pronounced disorders of the serum biochemistry in contrast to young rats. 30% hepatectomy has produced no age difference in the rate of hepatic regeneration, while this parameter in 70% hepatic resection in young rats is superior to that of old rats. Hepatectomy in young rats leads to MSC recruitment, hepatocyte precursors, endothelial and epithelial progenitor cells into the hepatic parenchyma, increases the plasticity of plasma and mitochondrial membranes of hepatocytes. While in old rats, the recruitment of MSC, hepatocyte precursors and endothelial progenitor cells into the injured liver is disrupted and the rigidity of the mitochondrial membranes of hepatocytes increases.
... Indikator yang diamati terhadap gangguan fungsi hati adalah aktivitas enzim transaminase yang meliputi SGPT dan SGOT. Menurut Kholodenko & Yarygin (2016), enzim transaminase merupakan enzim intraseluler, sehingga jika terjadi kerusakan sel akibat adanya suatu gangguan, maka aktivitasnya akan meningkat. Berdasarkan hasil penelitian, pemberian dosis parasetamol yang berlebih menyebabkan peningkatan nilai SGOT dan SGPT. ...
... Kelompok kontrol pelarut CMC 0,5% tetap mengalami penurunan nilai SGOT dan SGPT namun tidak signifikan. Penurunan tersebut disebabkan hati dapat melakukan regenerasi yang dipicu oleh hepatosit, sel Kupffer, dan sel punca, sehingga dapat pulih dari kerusakan (Kholodenko & Yarygin, 2016). ...
Lakum fruit (Cayratia trifolia L. (Domin)) has secondary metabolite compounds that are beneficial to health, one of which is a hepatoprotector. This study was conducted to prove the potential of hepatoprotective activity of lakum fruit methanol extract based on the value of SGPT and SGOT enzyme. The research method used a pre-posttest randomized control group design with a sample of 35 male rats divided into five treatment groups: solvent control group (CMC 0.5%); positive control group (HEPA-Q®); treatment group extract (0,575; 1,15; 1,725 mg/g BW). The treatment of induction of paracetamol and methanol extract of Cayratia trifolia fruit was carried out for 7 days respectively. The results showed that the dose of 1,15 mg/g BW of Cayratia trifolia fruit methanol extract had the most effective deterioration of SGOT and SGPT values with a percentage reduction of SGOT of 49.3% and SGPT of 51.8% (p <0.05) which approached control positive (HEPA-Q®). Based on the research conducted, methanol extract of Cayratia trifolia fruit has the potential to be hepatoprotective.
... The hepatic tissue has a high and dynamic metabolic capacity, being responsible for synthesizing essential biomolecules to the body homeostasis and act on the metabolization and inactivation of several harmful substances that may promote systemic damage (Adeva-Andany et al., 2016;Rui, 2014). Due to intense exposure to these agents, the hepatic parenchyma is susceptible to a great number of cellular injuries that may lead to tissue degeneration (Kholodenko and Yarygin, 2017;Sharma and Nagalli, 2022). Despite its regenerative potential, in many pathological cases, the level of tissue destruction is so intense that it becomes irreversible (Pinzani et al., 2011). ...
Hepatic microenvironment plays an essential role in liver regeneration, providing the necessary conditions for cell proliferation, differentiation and tissue rearrangement. One of the key factors for hepatic tissue reconstruction is the extracellular matrix (ECM), which through collagenous and non-collagenous proteins provide a three-dimensional structure that confers support for cell adhesion and assists on their survival and maintenance. In this scenario, placental ECM may be eligible for hepatic tissue reconstruction, once these scaffolds hold the major components required for cell support. Therefore, this preliminary study aimed to access the possibility of mouse embryonic stem cells differentiation into hepatocyte-like cells on placental scaffolds in a three-dimensional dynamic system using a Rotary Cell Culture System. Following a four-phase differentiation protocol that simulates liver embryonic development events, the preliminary results showed that a significant quantity of cells adhered and interacted with the scaffold through outer and inner surfaces. Positive immunolabelling for alpha fetus protein and CK7 suggest presence of hepatoblast phenotype cells, and CK18 and Albumin positive immunolabelling suggest the presence of hepatocyte-like phenotype cells, demonstrating the presence of a heterogeneous population into the recellularized scaffolds. Periodic Acid Schiff-Diastase staining confirmed the presence of glycogen storage, indicating that differentiate cells acquired a hepatic-like phenotype. In conclusion, these preliminary results suggested that mouse placental scaffolds might be used as a biological platform for stem cells differentiation into hepatic-like cells and their establishment, which may be a promissing biomaterial for hepatic tissue reconstruction.
... In the case of liver resection, studies have demonstrated that the restoration of the liver mass is mainly due to the compensatory hypertrophy and hyperplasia of the remaining hepatocytes [40,41]. ...
Over 40,000 patients in the United States are estimated to suffer from end-stage liver disease and acute hepatic failure, for which liver transplantation is the only available therapy. Human primary hepatocytes (HPH) have not been employed as a therapeutic tool due to the difficulty in growing and expanding them in vitro, their sensitivity to cold temperatures, and tendency to dedifferentiate following two-dimensional culture. The differentiation of human-induced pluripotent stem cells (hiPSCs) into liver organoids (LO) has emerged as a potential alternative to orthotropic liver transplantation (OLT). However, several factors limit the efficiency of liver differentiation from hiPSCs, including a low proportion of differentiated cells capable of reaching a mature phenotype, the poor reproducibility of existing differentiation protocols, and insufficient long-term viability in vitro and in vivo. This review will analyze various methodologies being developed to improve hepatic differentiation from hiPSCs into liver organoids, paying particular attention to the use of endothelial cells as supportive cells for their further maturation. Here, we demonstrate why differentiated liver organoids can be used as a research tool for drug testing and disease modeling, or employed as a bridge for liver transplantation following liver failure.
... Trauma, viral and toxic attacks can easily lead to liver injury, which activates the quiescent hepatocytes and brings them back into the cellular proliferation phase. When compensatory hyperplasia of activated hepatocytes is insufficient to restore liver mass, liver stem/progenitor cells begin to proliferate and differentiate to perform an alternative regenerative function (Kholodenko and Yarygin, 2017). However, liver regeneration capacity is usually impaired in liver diseases such as fatty liver, hepatitis, and post-hepatectomy liver failure. ...
Background:
The liver is renowned for its remarkable regenerative capacity to restore its structure, size and function after various types of liver injury. However, in patients with end-stage liver disease, the regenerative capacity is inhibited and liver transplantation is the only option. Considering the limitations of liver transplantation, promoting liver regeneration is suggested as a new therapeutic strategy for liver disease. Traditional Chinese medicine (TCM) has a long history of preventing and treating various liver diseases, and some of them have been proven to be effective in promoting liver regeneration, suggesting the therapeutic potential in liver diseases.
Purpose:
This review aims to summarize the molecular mechanisms of liver regeneration and the pro-regenerative activity and mechanism of TCM formulas, extracts and active ingredients.
Methods:
We conducted a systematic search in PubMed, Web of Science and the Cochrane Library databases using "TCM", "liver regeneration" or their synonyms as keywords, and classified and summarized the retrieved literature. The PRISMA guidelines were followed.
Results:
Forty-one research articles met the themes of this review and previous critical studies were also reviewed to provide essential background information. Current evidences indicate that various TCM formulas, extracts and active ingredients have the effect on stimulating liver regeneration through modulating JAK/STAT, Hippo, PI3K/Akt and other signaling pathways. Besides, the mechanisms of liver regeneration, the limitation of existing studies and the application prospect of TCM to promote liver regeneration are also outlined and discussed in this review.
Conclusion:
This review supports TCM as new potential therapeutic options for promoting liver regeneration and repair of the failing liver, although extensive pharmacokinetic and toxicological studies, as well as elaborate clinical trials, are still needed to demonstrate safety and efficacy.
