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Human Liver

Weighing, on average, about three pounds in an adult, the liver is the largest internal organ. Under normal conditions, the liver is located on the right side of the body, under the ribs. In a condition called situs inversus, the liver is located on the left side.

human liver

With jaundice, the skin and whites of the eyes turn yellow because of too much bilirubin in the blood. Bilirubin is a yellow waste product the liver gets rid of when it breaks down red blood cells. Higher levels of bilirubin indicate a possible problem in the liver.

The liver is both an organ and a gland that performs hundreds of functions vital to human life. Many common conditions and diseases can damage the liver, but you can take steps to protect it. Talk to a healthcare professional if you have any symptoms, especially jaundice or pain in your belly.

The main criterion for evaluation of the value of hepatic cells in basic research or pharmacological studies is the expression of typical hepatic functions and metabolic pathways. Important functions of the liver include: (i) metabolism of endogenous substrates (e.g. cell products) and exogenous compounds (e.g. drugs, chemicals); (ii) regulation of amino acids, carbohydrates, and fatty acids, (iii) synthesis of proteins, such as albumin or transferrin; and (iv) activation of inflammatory and immune reactions upon liver injury due to disease, drug, or toxin exposure.

Depending on the study aim and design, the cell type used in hepatic in vitro research has to fulfill each or some of those functions to reflect the situation in the native organ in vivo. Furthermore, preservation of hepatocyte functionality over several hours (e.g. for short-term studies on drug metabolism) or up to several days or even weeks (e.g. for long-term studies on subacute or subchronic drug toxicity) is needed to acquire relevant data. Since the stability and maintenance of the differentiated state of liver cells depends on both, the cell type used and the method of cultivation (e.g. 2D cultures or complex 3D cultures), the choice of culture model in association with a specific hepatic cell source is critical for the success of individual hepatic in vitro studies. In addition, standardization of experiments is required to provide reproducible and reliable results from in vitro hepatic cultures. Thus, a constant quality of the cells needs to be ensured and verified by appropriate quality control measures. Finally, the availability of cells is a critical factor for the usage of certain cell types in in vitro research. This aspect is of particular importance for studies requiring large numbers of cells and/or experiments.

Processing of cells derived from different sources for the generation of human in vitro liver cell culture models. Major cell types include primary human hepatocytes (PHH), hepatoma cell lines, adult stem cells, human embryonic stem cells (hESC), and induced pluripotent stem cells (iPSC). Whereas PHH can be used for in vitro cultivation immediately after isolation, liver cell lines or stem cells need to be expanded and/or differentiated prior to their use in experiments. (A color version of this figure is available in the online journal.)

The cell isolation outcome depends on donor characteristics and intraoperative factors, in addition to tissue processing and cell isolation conditions.8 Lee et al. investigated the PHH isolation outcome of 1034 donors.9 The study revealed that cell viability was significantly influenced by donor characteristics, such as age, body mass index, liver fat content, liver damage (e.g. fibrosis), and the resulting changes in the clinical parameters in the blood (e.g. liver enzymes, bilirubin). In addition, the blood coagulability, warm ischemic time in vivo during surgery, and cold ischemic time in vitro during tissue transport were identified as critical factors for the success of the isolation. Surgical procedures which involve increased warm ischemia times, e.g. due to clamping during surgery, can lead to an impaired yield and viability of PHH.8 In contrast, portal vein embolization showed no negative influence on isolation outcome,10 and the yield of PHH was even increased with warm ischemia times ex vivo, and when the patients received chemotherapeutic treatment.9 Furthermore, the type of disease was identified to have a significant impact upon the cell yield.11 In particular, alcohol-related liver diseases were shown to cause alterations in hepatocyte function in culture.11

The need for both efficient medium and oxygen transfer to the cells while allowing 3D tissue assembly is addressed by a dynamic four-compartment 3D bioreactor technology for high-density liver cell culture.60 The bioreactor structure is illustrated in Figure 3. Cells are cultured within a 3D scaffold made of different types of hollow-fiber capillaries, which are arranged in two or more layers composed of medium and oxygen capillaries. The capillary membranes enable the transfer of solutes via hydrophilic membranes and gas exchange via hydrophobic membranes, in addition to their function as an adhesion matrix for the cells cultured between the capillaries. By this way, four compartments (two counter-currently perfused medium compartments, one gas compartment and the cell compartment) are created, which form multiple repetitive units for the decentralized supply of cell aggregates with low gradients. To ensure constant culture conditions, bioreactors are operated in a perfusion device, which enables electronic control of temperature, medium perfusion rates, gas mixture, and gas supply.

Miniaturized four-compartment bioreactor for high-density perfusion culture of liver cells.66 The bioreactor technology is based on two or more layers of hollow-fiber capillaries, which serve for counter-current medium perfusion (marked in red and blue) and air/CO2 supply (yellow). Cells are inoculated into the extra-capillary space (cell compartment). The schematic pictures on the right show the capillary structure viewed from top before and after cell seeding. (A color version of this figure is available in the online journal.)

Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2+CD9+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα+ collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.

P.R. performed experimental design, tissue procurement, data generation, data analysis and interpretation, and manuscript preparation; R.D. performed experimental design, data generation and data analysis; E.F.D., K.P.M., B.E.P.H., M.B., J.A.M. and N.T.L. performed data generation and analysis; J.R.P. generated the interactive online browser; M.E. and R.V.-T. assisted with CellPhoneDB analyses and critically appraised the manuscript; T.J.K. performed pathological assessments and provided intellectual contribution; N.O.C., J.A.F. and P.N.N. provided intellectual contribution; C.J.W. performed tissue procurement, data generation, interpretation and intellectual contribution; J.R.W.-K. performed computational analysis with assistance from J.R.P. and R.S.T. and advice from C.P.P., J.C.M. and S.A.T.; J.R.W.-K. also helped with manuscript preparation, and C.P.P., J.C.M. and S.A.T. critically appraised the manuscript; E.M.H., D.J.M. and S.J.W. procured human liver tissue and critically appraised the manuscript. J.P.I., F.T. and J.W.P. provided intellectual contribution and critically appraised the manuscript; N.C.H. conceived the study, designed experiments, interpreted data and prepared the manuscript.

a, Lineage signature expression across 66,135 liver-resident cells from healthy (n = 5) and cirrhotic (n = 5) human livers (red, high; blue, low). b, Dot plot annotating liver-resident cell clusters by lineage signature. Circle size indicates cell fraction expressing signature greater than mean; colour indicates mean signature expression (red, high; blue, low). c, Violin plots of the number of unique genes (left), number of total UMIs (middle) and mitochondrial gene fraction (right) across 66,135 liver-resident cells from healthy (n = 5) and cirrhotic (n = 5) livers. Black lines denote the median. d, Pie charts of the proportion of cell lineage per liver sample. e, Box and whisker plots of the agreement in expression profiles across healthy (n = 5) and cirrhotic (n = 5) liver samples, as in Extended Data Fig. 1i. f, t-SNE visualization of liver-resident cells per liver sample, with cirrhotic samples annotated by aetiology of underlying liver disease. ALD, alcohol-related liver disease; PBC, primary biliary cholangitis.

a, Clustering of 36,900 T cells and ILCs (left) from healthy (n = 5) and cirrhotic (n = 5) human livers, annotating the injury condition (right). NK, natural killer cell; cNK, cytotoxic NK cell. b, Fractions of T cell and ILC subpopulations in healthy (n = 5) and cirrhotic (n = 5) livers. c, Selected gene expression in 36,900 T cells and ILCs. d, Heat map of T cell and ILC cluster marker genes (colour-coded by cluster and condition), with exemplar genes labelled (right). Columns denote cells; rows denote genes. e, t-SNE visualizations of downsampled T cell and ILC dataset (7,380 cells from healthy (n = 5) and cirrhotic (n = 5) human livers) before and after imputation (scImpute); annotating data used for visualization and clustering, inferred lineage and injury condition. No additional heterogeneity was observed after imputation. f, Clustering 2,746 B cells and plasma cells (left) from healthy (n = 5) and cirrhotic (n = 5) human livers, annotating the injury condition (right). g, Heat map of B cell and plasma cell cluster marker genes (colour-coded by cluster and condition), with exemplar genes labelled (right). Columns denote cells; rows denote genes. h, Fractions of B cell and plasma cell subpopulations in healthy (n = 5) and cirrhotic (n = 5) livers. Data are mean s.e.m. P values determined by Wald test (b). 041b061a72


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