The Liver and Hepatic Cells

Hepatocytes are polarized epithelial cells, possessing apical (canalicular) and basolateral (sinusoidal) plasma membrane domains. They are the parenchymal cells of the liver, comprising at least 60% of liver cells and about 80% of cell mass[2], [3], [4]. The functions of hepatocytes are rely on establishment and maintenance of hepatocyte polarity[2]. Hepatocyte polarity organizes and maintains the hepatocyte’s plasma membrane into distinct apical (canalicular) and basolateral (sinusoidal) domains, enabling different functions at both domains. The apical membranes of adjacent hepatocytes form the bile canaliculus (BC), the smallest, capillary-like branch of the bile duct[4], [5]. Through the bile canaliculus, bile components secreted by hepatocytes are collected and flow toward larger bile duct. The basolateral (sinusoidal) membranes serve as the functional basal surfaces of hepatocytes, since these cells lack a dense basal lamina[5], [6]. Instead, hepatocytes are enveloped by a loose extracellular matrix in the space of Disse[6], which lies between the hepatocytes and the fenestrated, discontinuous liver sinusoidal endothelial cells. This configuration allows plasma from the sinusoid to reach the hepatocyte basal membranes, enabling efficient nutrient exchange, detoxification and metabolism, and signaling communication.

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Human Hepatocytes ARP0068
Rat Hepatocytes ARP0233
Mouse Hepatocytes ARP0476
Rabbit Hepatocytes ARP0720

Liver sinusoidal endothelial cells (LSECs) are high specialized cells, playing key role in liver homeostasis under both physiological and pathological conditions[7], [8], [9]. They represent the majority of endothelial cells in the liver[8] and are the main structural component of the liver sinusoid, which is a fenestrated, capillary-like blood vessel for exchange of substance between the space of Disse and the blood. They form a highly permeable barrier facing the basolateral membranes of hepatocytes, separated from them by the space of Disse, where hepatic stellate cells and other immune active cells are located[7], [10], [11]. These cells have non-diaphragmed fenestrae and lack basement membrane, which make them the most permeable mammalian endothelial cells for efficient exchange of macromolecules[7], [8], [9], [12]. In physiological conditions, LSECs act as vascular regulators, guardians against fibrosis, and mediators of regeneration. They regulate hepatic vascular tone, maintaining low portal pressure during fluctuating blood flow. Differentiated LSECs was shown to maintain the quiescence of hepatic stellate cells (HSCs) through inhibition of HSCs activations and reversing activated HSCs, preventing intrahepatic vasoconstriction and fibrosis[7], [9], [10]. In pathological conditions, LSECs become undifferentiated (fail to mature) or capillarized, losing the ability to maintain HSCs quiescence, contributing to angiogenesis and vasoconstriction thus driving liver fibrosis progression and chronic inflammation[7], [10], further leading to carcinogenesis[13]. Moreover, research on LSECs extend to liver regeneration. Liver sinusoidal endothelial cells participate in liver regeneration after acute injury or partial hepatectomy by renewing from LSECs or progenitors.

Recommended Products - Liver Sinusoidal Endothelial Cells
Human Liver Sinusoidal Endothelial Cells ARP0066
Rat Liver Sinusoidal Endothelial Cells ARP0235
Mouse Liver Sinusoidal Endothelial Cells ARP0478
Rabbit Liver Sinusoidal Endothelial Cells ARP0722

Hepatic Stellate Cells (HSCs), also known as Ito cells, lipocytes, vitamin A-storing cells, fat-storing cells, are mesenchymal cells in the space of Disse, between hepatocytes and sinusoidal endothelial cells, that support hepatocellular functions and mediate the liver injury response[14], [15]. They are liver pericytes that wrap around the sinusoids and regulate sinusoidal blood flow by contracting and relaxing in response to ET-1/eNOS signaling from LSECs. [16], [17]. In a healthy liver, HSCs are quiescent (qHSCs) and exhibit a modest protein-synthetic machinery (moderately developed rough endoplasmic reticulum and small Golgi complex), and their long cytoplasmic processes extend around the sinusoids[18] to sense signals, store vitamin A, and regulate sinusoidal microenvironment. 80% of the whole body retinoids (vitamin A derivates) is stored in lipid droplets within HSCs cytoplasm, and both transport and storage of vitamin A are regulated by HSCs[14], [19]. HSCs also have the ability to express and secrete basement membrane components, such as type IV collagen, laminin, and proteoglycans to support sinusoidal structure and endothelial integrity[20]. This synthesis is balanced by expression of matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, and their inhibitors (TIMPs), enabling controlled turnover to prevent excessive deposition or degradation in the healthy liver. During liver injury, hepatic stellate cells are activated by directly sensing toxins, oxidative stress, mechanical stiffness, and ECM alterations, and by receiving activating signals from injured liver cells, such as hepatocytes, LESCs, and Kuffer Cells. Upon activation, HSCs lose the vitamin A stores and transdifferentiate into contractile, proliferative and fibrogenic myofibroblast-like cells[21], [22]. This process is accompanied by alternations in the expression of hundreds of genes, such as a remarkable increase of α-smooth muscle actin (α-SMA, ACTA2), desmin (DES), and various collagens[23], [24]. Activated HSCs secrete collagen I and III (fibrillar collagens) which gradually replace collagen IV (a non-fibrillar collagen) in the basement membrane, leading to increased tissue stiffness[22], [25]. They also produce lysyl oxidase (LOX), LOX-like proteins (LOXL), and transglutaminase to mediate the crosslink collagen crosslinking in the extracellular space, and they upregulate TIMPs to suppress the activity of MMPs, thereby inhibiting ECM degradation[20]. Persistent fibrogenic signaling maintains HSCs in an activated state, resulting in excessive ECM accumulation that distorts liver architecture, reduces hepatic elasticity, impairs sinusoidal blood flow, and increases the risk of organ failure and hepatocarcinogenesis.

Products of Hepatic Stellate Cells

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[8] T. Su et al., “Single-Cell Transcriptomics Reveals Zone-Specific Alterations of Liver Sinusoidal Endothelial Cells in Cirrhosis,” Cell. Mol. Gastroenterol. Hepatol., vol. 11, no. 4, pp. 1139–1161, 2021, doi: 10.1016/j.jcmgh.2020.12.007.

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[10] Q. He et al., “Role of liver sinusoidal endothelial cell in metabolic dysfunction-associated fatty liver disease,” Cell Commun. Signal., vol. 22, no. 1, p. 346, June 2024, doi: 10.1186/s12964-024-01720-9.

[11] E. M. Brunt et al., “Pathology of the liver sinusoids,” Histopathology, vol. 64, no. 7, pp. 907–920, June 2014, doi: 10.1111/his.12364.

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[13] Z. Yu et al., “Nano delivery of simvastatin targets liver sinusoidal endothelial cells to remodel tumor microenvironment for hepatocellular carcinoma,” J. Nanobiotechnology, vol. 20, no. 1, p. 9, Dec. 2022, doi: 10.1186/s12951-021-01205-8.

[14] H. Senoo, N. Kojima, and M. Sato, “Vitamin A‐Storing Cells (Stellate Cells),” in Vitamins & Hormones, vol. 75, Elsevier, 2007, pp. 131–159. doi: 10.1016/S0083-6729(06)75006-3.

[15] B. J. Potter, “Components of the Hepatic System,” in Reference Module in Biomedical Sciences, Elsevier, 2019, p. B9780128012383049357. doi: 10.1016/B978-0-12-801238-3.04935-7.

[16] W. Kwok, S. H. Lee, C. Culberson, K. Korneszczuk, and M. G. Clemens, “Caveolin-1 mediates endotoxin inhibition of endothelin-1-induced endothelial nitric oxide synthase activity in liver sinusoidal endothelial cells,” Am. J. Physiol.-Gastrointest. Liver Physiol., vol. 297, no. 5, pp. G930–G939, Nov. 2009, doi: 10.1152/ajpgi.00106.2009.

[17] C. Hellerbrand, “Hepatic stellate cells—the pericytes in the liver,” Pflüg. Arch. - Eur. J. Physiol., vol. 465, no. 6, pp. 775–778, June 2013, doi: 10.1007/s00424-012-1209-5.

[18] L. Atzori, G. Poli, and A. Perra, “Hepatic stellate cell: A star cell in the liver,” Int. J. Biochem. Cell Biol., vol. 41, no. 8–9, pp. 1639–1642, Aug. 2009, doi: 10.1016/j.biocel.2009.03.001.

[19] M. Sato, S. Suzuki, and H. Senoo, “Hepatic Stellate Cells: Unique Characteristics in Cell Biology and Phenotype,” Cell Struct. Funct., vol. 28, no. 2, pp. 105–112, 2003, doi: 10.1247/csf.28.105.

[20] O. Khomich, A. V. Ivanov, and B. Bartosch, “Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis,” Cells, vol. 9, no. 1, p. 24, Dec. 2019, doi: 10.3390/cells9010024.

[21] S. L. Friedman, “Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver,” Physiol. Rev., vol. 88, no. 1, pp. 125–172, Jan. 2008, doi: 10.1152/physrev.00013.2007.

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[27] J. M. Crawford and A. D. Burt, “Anatomy, pathophysiology and basic mechanisms of disease,” in MacSween’s Pathology of the Liver, Elsevier, 2012, pp. 1–77. doi: 10.1016/B978-0-7020-3398-8.00001-5.

[28] L. J. Dixon, M. Barnes, H. Tang, M. T. Pritchard, and L. E. Nagy, “Kupffer Cells in the Liver,” in Comprehensive Physiology, 1st ed., Y. S. Prakash, Ed., Wiley, 2013, pp. 785–797. doi: 10.1002/cphy.c120026.

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