Does Mechanocrine Signaling by Liver Sinusoidal Endothelial Cells Offer New Opportunities for the Development of Anti-fibrotics?

Soydemir, Sumeyye; Comella, Olivia; Abdelmottaleb, Dina; Pritchett, James

doi:10.3389/fmed.2019.00312

Cited by 14 publications

(11 citation statements)

References 69 publications

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“…These pertubations in mechano-sensing by LSEC drive fibrotic processes ( Ford et al, 2015 ; Soydemir et al, 2019 ) and changes in hepatic blood pressure and liver stiffness occur soon after hepatic injury ( Georges et al, 2007 ). Biophysical characteristics of the ECM and matrix stiffness are key mechanisms in mediating HSC activation contributing to fibrogenesis ( Sakata et al, 2004 ; Olsen et al, 2011 ).…”

Section: Lsec Pathophysiologymentioning

confidence: 99%

“…Briefly, authors showed that expression of Notch-dependent transcription factors HES1 and HEY1 resulted in neutrophil recruitment via CXCL1 secretion, a mechanism thought to drive microthrombus formation and portal hypertension in mice. Additionally, activated HSC further increase tissue stiffness by depositing more ECM, further driving mechano-activation ( Soydemir et al, 2019 ). Drugs that intervene with this mechano-sensitive positive feedback cycle could show therapeutic promise for the treatment of fibrosis.…”

Section: Lsec Pathophysiologymentioning

confidence: 99%

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The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

2020

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Liver sinusoidal endothelial cells (LSEC) form a unique barrier between the liver sinusoids and the underlying parenchyma, and thus play a crucial role in maintaining metabolic and immune homeostasis, as well as actively contributing to disease pathophysiology. Whilst their endocytic and scavenging function is integral for nutrient exchange and clearance of waste products, their capillarisation and dysfunction precedes fibrogenesis. Furthermore, their ability to promote immune tolerance and recruit distinct immunosuppressive leukocyte subsets can allow persistence of chronic viral infections and facilitate tumour development. In this review, we present the immunological and barrier functions of LSEC, along with their role in orchestrating fibrotic processes which precede tumourigenesis. We also summarise the role of LSEC in modulating the tumour microenvironment, and promoting development of a pre-metastatic niche, which can drive formation of secondary liver tumours. Finally, we summarise closely inter-linked disease pathways which collectively perpetuate pathogenesis, highlighting LSEC as novel targets for therapeutic intervention.

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Section: Lsec Pathophysiologymentioning

confidence: 99%

Section: Lsec Pathophysiologymentioning

confidence: 99%

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

2020

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“…On top of this mechanism, the pressure and the flow are actively controlled at the sinusoidal level: LSEC release vasoactive substances, such as the potent vasodilator nitric oxide (NO) [ 23 ], as well as the vasoconstrictive endothelin-1 that act in a paracrine fashion on the contractile “pericyte-like” hepatic stellate cells (HSC) [ 11 ]. HSC in the space of Disse embrace the sinusoids with their cytoplasmatic extensions, and by their contraction, regulate the sinusoidal resistance to intrahepatic blood flow [ 24 , 25 ] ( Figure 1 ). Vasodilative and vasoconstrictive molecules are secreted in response to changes in shear stress.…”

Section: Regulation Of the Liver Blood Tonementioning

confidence: 99%

Critical Role of LSEC in Post-Hepatectomy Liver Regeneration and Failure

Rudder¹,

Dili

Stärkel

et al. 2021

IJMS

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Liver sinusoids are lined by liver sinusoidal endothelial cells (LSEC), which represent approximately 15 to 20% of the liver cells, but only 3% of the total liver volume. LSEC have unique functions, such as fluid filtration, blood vessel tone modulation, blood clotting, inflammatory cell recruitment, and metabolite and hormone trafficking. Different subtypes of liver endothelial cells are also known to control liver zonation and hepatocyte function. Here, we have reviewed the origin of LSEC, the different subtypes identified in the liver, as well as their renewal during homeostasis. The liver has the exceptional ability to regenerate from small remnants. The past decades have seen increasing awareness in the role of non-parenchymal cells in liver regeneration despite not being the most represented population. While a lot of knowledge has emerged, clarification is needed regarding the role of LSEC in sensing shear stress and on their participation in the inductive phase of regeneration by priming the hepatocytes and delivering mitogenic factors. It is also unclear if bone marrow-derived LSEC participate in the proliferative phase of liver regeneration. Similarly, data are scarce as to LSEC having a role in the termination phase of the regeneration process. Here, we review what is known about the interaction between LSEC and other liver cells during the different phases of liver regeneration. We next explain extended hepatectomy and small liver transplantation, which lead to “small for size syndrome” (SFSS), a lethal liver failure. SFSS is linked to endothelial denudation, necrosis, and lobular disturbance. Using the knowledge learned from partial hepatectomy studies on LSEC, we expose several techniques that are, or could be, used to avoid the “small for size syndrome” after extended hepatectomy or small liver transplantation.

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“…The effects of mechanical force on the functional properties of extrahepatic vascular endothelium have been well demonstrated, as previously reviewed (29,60,179), while the role of hepatic endothelium in mechanical sensing is less well understood (83,153). LSECs are subjected to two major forces (135): 1) cyclic stretch resulted from mechanical distortion and tension of the vessel wall and 2) fluid shear stress caused by blood flow.…”

Section: Mechanotransductionmentioning

confidence: 99%

New aspects of hepatic endothelial cells in physiology and nonalcoholic fatty liver disease

Sun

Harris

2020

American Journal of Physiology-Cell Physiology

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The liver is the central metabolic hub for carbohydrate, lipid, and protein metabolism. It is composed of four major types of cells, including hepatocytes, endothelial cells (ECs), Kupffer cells, and stellate cells. Hepatic ECs are highly heterogeneous in both mice and humans, representing the second largest population of cells in liver. The majority of them line hepatic sinusoids known as liver sinusoidal ECs (LSECs). The structure and biology of LSECs and their roles in physiology and liver disease were reviewed recently. Here, we do not give a comprehensive review of LSEC structure, function, or pathophysiology. Instead, we focus on the recent progress in LSEC research and other hepatic ECs in physiology and nonalcoholic fatty liver disease and other hepatic fibrosis-related conditions. We discuss several current areas of interest, including capillarization, scavenger function, autophagy, cellular senescence, paracrine effects, and mechanotransduction. In addition, we summarize the strengths and weaknesses of evidence for the potential role of endothelial-to-mesenchymal transition in liver fibrosis.

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Does Mechanocrine Signaling by Liver Sinusoidal Endothelial Cells Offer New Opportunities for the Development of Anti-fibrotics?

Cited by 14 publications

References 69 publications

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

Critical Role of LSEC in Post-Hepatectomy Liver Regeneration and Failure

New aspects of hepatic endothelial cells in physiology and nonalcoholic fatty liver disease

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