Liver Sinusoidal Endothelial Cells at the Crossroad of Iron Overload and Liver Fibrosis

Abstract

Significance Liver fibrosis results from different etiologies and represents one of the most serious health issues worldwide. Fibrosis is the outcome of chronic insults on the liver and is associated with several factors, including abnormal iron metabolism. Recent AdvancesMultiple mechanisms underlying the pro-fibrogenic role of iron have been proposed. The pivotal role of Liver Sinusoidal Endothelial Cells (LSECs) in iron level regulation, as well as their morphological and molecular de-differentiation occurring in liver fibrosis, have encouraged research on LSECs as prime regulators of very early fibrotic events.Importantly, normal differentiated LSECs may act as gatekeepers of fibrogenesis by maintaining the quiescence of Hepatic Stellate Cells (HSCs), while LSECs capillarization precedes the onset of liver fibrosis. Critical IssuesIn the present review, the morphological and molecular alterations occurring in LSECs following liver injury are addressed in an attempt to highlight how vascular dysfunction promotes fibrogenesis. In particular, we discuss in depth how a vicious loop can be established in which iron-dysregulation and LSEC de-differentiation synergize to exacerbate and promote the progression of liver fibrosis.Future Directions LSECs, due to their pivotal role in early liver fibrosis and iron homeostasis, show great promises as a therapeutic target. In particular, new strategies can be devised for restoring LSECs differentiation and thus their role as regulators of iron homeostasis, hence preventing the progression of liver fibrosis or, even better, promoting its regression.

Effects of aging on the severity of liver injury in mice with iron overload

“…The fenestration of liver sinusoidal endothelial cells (LSECs) is regarded as a dynamic structure that can be easily affected by nearby environment. [41][42][43] Similar to the sinusoidal defenestration change caused by iron overload, 31,44 our results showed a loss of fenestration in the iron overload groups. In particular, almost no fenestration was observed in the super-old iron-overloaded mice.…”

Secondary iron overload induces chronic pancreatitis and ferroptosis of acinar cells in mice

“…Previous studies have found that iron overload can lead to the atrophy and dysfunction of organs such as the liver, heart, muscles or brain ( 33 , 34 ). In the present study, iron accumulation in the pancreas may be associated with pancreatic dysfunction.…”

Extracellular vesicles targeting non-parenchymal cells: the therapeutical effect on liver fibrosis

“…29 30 Furthermore, dedifferentiated LSECs play a role in generating the inflammatory milieu and altering intrahepatic immunity, promoting fibrosis. 31 Fibrosis is considered a dynamic and reversible process termed fibrosis resolution/regression when the underlying causes are eliminated. Coculturing differentiated LSECs with activated HSCs and using an sGC activator to maintain LSEC differentiation can lead to the reversion of activated HSCs back to a quiescent state.…”