Endothelial Cells and Mitochondria: Two Key Players in Liver Transplantation

Abstract

Building the inner layer of our blood vessels, the endothelium forms an important line communicating with deeper parenchymal cells in our organs. Previously considered passive, endothelial cells are increasingly recognized as key players in intercellular crosstalk, vascular homeostasis, and blood fluidity. Comparable to other cells, their metabolic function strongly depends on mitochondrial health, and the response to flow changes observed in endothelial cells is linked to their mitochondrial metabolism. Despite the direct impact of new dynamic preservation concepts in organ transplantation, the impact of different perfusion conditions on sinusoidal endothelial cells is not yet explored well enough. This article therefore describes the key role of liver sinusoidal endothelial cells (LSECs) together with their mitochondrial function in the context of liver transplantation. The currently available ex situ machine perfusion strategies are described with their effect on LSEC health. Specific perfusion conditions, including perfusion pressure, duration, and perfusate oxygenation are critically discussed considering the metabolic function and integrity of liver endothelial cells and their mitochondria.

Keywords: endothelial cells; ischemia-reperfusion injury; machine perfusion; mitochondria; reactive oxygen species; shears stress.

Figure 1

Role of mitochondria in various liver cells during ischemia-reperfusion injury (IRI). All types of liver cells have different metabolic capacity and subsequent mitochondria. Although hepatocytes contain the highest number of mitochondria, this subcellular powerhouse plays an equally key role in all other cells. With prolonged ischemia, the electron transfer is on hold and the TCA cycle and other metabolic processes shift to anaerobic features, accumulating potentially detrimental metabolites, such as succinate. When oxygen is reintroduced, high succinate levels trigger an uncoordinated and retrograde electron flow with the release of reactive oxygen species (ROS) from all affected mitochondria. This initial trigger is the key instigator of the entire IRI cascade with direct damage to affected cells and indirect injury of neighboring cells initially not severely injured. The activated microenvironment of a newly implanted liver in turn attracts circulating cells in the recipient’s blood, including neutrophils and platelets, which attach to SECs. ATP: Adenosine-trisphosphate; Cyt C: Cytochrome C; DAMPs: Danger-associated molecular patterns; ROS: Reactive oxygen species; SECs: Sinusoidal endothelial cells; TCA-cycle: Tricarboxylic acid cycle.

Figure 2

Proinflammatory liver microenvironment during reperfusion. The initial injury is triggered by mitochondria, either inside the corresponding liver SEC or by ROS molecules released from other cells. These instigator molecules are the first domino stope to initiate the IRI cascade. SECs are impaired in function through two mechanisms, initially by their own IRI and in a second wave once these cells are situated peripherally to initially damaged liver SECs that inflame their microenvironment with attachment of neutrophils and platelets leading to second hypoxia with an ongoing cascade of inflammation. Key mediators are mtROS, KLF2, NRF2, NO triggering the expression of ICAM and ECAM, and other cytokines interacting with macrophages and other recipient cells circulating through the microenvironment of the newly implanted liver. Various levels of liver SEC shear stress affect the expression of vasoconstrictive and vasodilative molecules (i.e., ET-1) that communicate with hepatic stellate cells (HSC) in the space of Disse. ECAM: Endothelial cell adhesion molecule; ICAM: Intercellular adhesion molecule; IRI: Ischemia reperfusion injury; KLF2: Kruppel-like factor 2; NO: Nitric oxide; NRF2: Nuclear factor erythroid 2–related factor 2 (regulator of cellular resistance towards oxidative stress); mtROS: Mitochondrial reactive oxygen species.

Figure 3

Link between blood flow, shear stress, and mitochondrial dysfunction. Different pathways of liver SEC injury are shown. Disturbed shear stress leads to mitochondrial injury in SECs, exposing hepatocytes and other parenchymal cells to additional inflammation and injury through a lack of proper SEC function and protection. During ischemia−reperfusion injury, mitochondria in other cells (i.e., hepatocytes and macrophages) also release ROS and DAMPs and promote the maintenance of inflammation in the microvascular environment. The ongoing inflammation leads to a high risk of further disturbed sinusoidal flows and obstruction with secondary hypoxia.