Liver sinusoidal endothelial cells (LSECs) are highly specialized liver endothelial cells that form a physical barrier between the blood and hepatocytes. They are the most abundant non-parenchymal hepatic cell population. LSECs play an important role in physiological, immunological, and regulatory cell functions. As chronic liver conditions advance, crosstalk between LSECs and other liver cells mediate responses to fibrosis and carcinogenesis.
Unique Characteristics of LSECs
As previously described, LSECs form a the barrier between the blood outside of the liver and hepatocytes and hepatic stellate cells within the liver. There are key characteristics of this specific type of cell that suggest its relevance in liver disease treatment.
- LSECs have a low proliferation rate and long life span.
- Bone marrow derived sinusoidal endothelial cells do not participate in LSEC turnover in a healthy liver, but are the main triggers of liver regeneration. They secrete VEGF and HGF, growth factors that are thought to promote regeneration.
- LSECs are highly permeable through the fenestrae, which serves as a channel for blood cells, metabolites, plasma proteins, pharmaceutical drugs, lipoproteins, and exosomes. These molecules are stored in the space of Disse, which contains a paravascular part of the blood plasma volume. The liver is “leaky” to large molecules, such as proteins, and this explains why fluid build-up, as a consequence of liver diseases, can contain too low or too high amounts of protein.
- LSECs have one of the highest endocytic capacities, meaning that LSECs play an important role in clearing waste from the blood. This property can be used to select LSECs by specifically targeting endocytic receptors.
- LSECs have been well studied, and “famous” LSEC genes include CD32B, which encodes a region of immunoglobulin G (IgG) antibodies.
- Another topical type of endothelial cell are brain microvascular endothelial cells (BMECs). BMECs form the blood-brain barrier, which serves as a dynamic barrier between the blood and the brain.
LSECs in Liver Diseases
LSECs are key components of liver disease initial and progression through four processes summarized below:
- Capillarization: Also known as dedifferentiation, this early event occurs in LSECs following liver injury. LSECs maintain hepatic stellate cell function, and vascular endothelial growth factor (VEGF) contributes to maintaining LSEC differentiation. Fibrogenesis, a precursor to fibrosis, is triggered by capillarization.
- Angiogenesis: Hepatic angiogenesis is the development of new vessels from preexisting vessels and occurs during liver fibrogenesis. Liver fibrosis enhances angiogenesis, and angiogenesis aggravates livery fibrosis. VEGF also famously regulates angiogenesis (Hint: tumorigenesis!)
- Angiocrine signals: These signals are paracrine factors produced by endothelial cells that ensure cellular homeostasis and balance stem cell growth and regeneration. LSECs regulate fibrosis through angiocrine signals.
- Vasoconstriction: Following capillarization, hepatic stellate cells are activated and collagen and fibrosis are produced. This change results in increased shear stress and results in vasoconstriction and higher intrahepatic resistance.
LSECs in Liver Regeneration
LSECs play a key role in liver regeneration after acute liver injury. They sense the shift in shear stress, and orchestrate the regeneration of different cell types by interacting with sinusoidal progenitor cells, platelets, and inflammatory cells.
LSECs in Inflammation and Infection
LSECs regulate liver inflammation in two key ways. First, LSECs serve as a physical barrier between the blood and the liver, and thus regulate leukocyte entrance into the liver. Second, LSECs can modulate lymphocyte behavior. In the presence of antigens, LSECs can induce the differentiation of T cells into regulatory T cells (Treg). This was proven in both in vitro and in vivo models . LSECs also have anti-inflammatory effects since they can increase the expression of IL-10, an anti-inflammatory cytokine.
Tempo-iLSEC™ Product (announced on March 15, 2023)
Tempo-iLSEC™ are human iPSC-derived liver sinusoidal endothelial cells. At Tempo Bioscience, we recently released this product along with three other iPSC-derived products to contribute to a more accurate human liver model. Tempo-iHepStellate™-iKupffer™-iLSEC™-iHep3D™ is the organoid formed out of these four new product offerings, and can accurately model Nonalcoholic Steatohepatitis (NASH), Nonalcoholic fatty liver disease (NAFLD), liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).
Johanne Poisson et al., Liver sinusoidal endothelial cells: Physiology and role in liver diseases. Journal of Hepatology 2017; 66(1):212-227.
Antonella Carambia et al., TGF-β-dependent induction of CD4+CD25+Foxp3+ Tregs by liver sinusoidal endothelial cells, Journal of Hepatology, 61(3): 594-599. https://www.sciencedirect.com/science/article/pii/S0168827814002906
Poisson J, Lemoinne S, Boulanger C, Durand F, Moreau R, Valla D, Rautou PE. Liver sinusoidal endothelial cells: Physiology and role in liver diseases. J Hepatol. 2017 Jan;66(1):212-227. doi: 10.1016/j.jhep.2016.07.009. Epub 2016 Jul 14. PMID: 27423426. https://pubmed.ncbi.nlm.nih.gov/27423426/