肝窦内皮细胞与肝再生

肝窦内皮细胞(liver sinusoidal endothelial cells,LSECs)是肝脏非实质细胞中数目最多的细胞,约占肝非实质细胞总数的70％,在表型、功能上与普通毛细血管内皮细胞有较大差异.有关LSECs在肝再生过程中作用的研究相对较少.近年来,关于LSECs再生行为及其与肝内其他细胞成分相互作用的研究结果提示其在肝再生和肝衰竭中具有重要作用,但具体机制尚未完全明确.现就LSECs的再生行为及其在肝再生中的作用,以及以LSECs为靶点干预肝再生等进行综述.     

肝窦内皮细胞与肝纤维化的关系

生理情况下，肝窦内皮细胞(LSEC)对肝脏稳态的维持起重要作用。而在肝脏病理损伤条件下,LSEC可通过改变其自身结构即毛细血管化对损伤做出反应，并加重肝损伤。此外,LSEC与肝脏中其他细胞的相互作用对肝纤维化的发生发展也有一定作用，其中与肝纤维化的主要效应细胞——肝星状细胞的交互作用占主体地位。本文主要阐述慢性肝损伤时LSEC在肝纤维化发生发展中的作用。     

肝窦内皮细胞与非酒精性脂肪性肝病的研究进展

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是一个与代谢综合征相关的日益扩大的健康问题.肝窦内皮细胞(liver sinusoidal endothelial cells,LSECs)是位于血液与其他肝细胞类型之间高度专业化的内皮细胞,由窗孔组成,具有高内吞能力,并在维持肝脏整体稳态中发挥重要作用.病理条件下LSECs可能是多种慢性肝病的关键事件.本篇综述介绍了LSECs的独特生理结构和功能,重点总结了NAFLD中LSECs的主要变化(包括肝窦毛细血管化、血管生成、血管收缩、促炎和促纤维化)及其发生机制,还涉及LSECs对NAFLD进展的影响,旨在说明LSECs靶向治疗对NAFLD具有潜在疗效.     

肝血窦内皮细胞在肝再生和肝纤维化发生中的作用

肝血窦内皮细胞是肝脏非实质细胞的主要组成细胞,是覆盖于肝窦的薄层扁平状细胞,表面富含窗孔,是肝窦和窦状间隙之间溶质交换的开放通道。肝血窦内皮细胞的分泌功能尤其是Wnt信号通路在维持Axin2+源性肝细胞的自我更新、促进肝部分切除或肝损伤时肝再生中均发挥重要的保护作用。肝损伤时,肝血窦内皮细胞结构发生改变,表现为窗孔消失和内皮下基底膜的形成,即肝窦毛细血管化。肝窦毛细血管化既是肝纤维化发生的前奏,也会促进肝纤维化的进展。肝窦内皮细胞在不同生理或病理状态下可通过信号通路的转换实现肝再生和肝纤维化调控作用的转换。肝血窦内皮细胞参与肝再生和肝纤维化机制的深入认识有望为慢性肝病的防治提供新的治疗靶点。     

肝窦内皮细胞在非酒精性脂肪性肝病中的研究进展

非酒精性脂肪肝性肝病(NAFLD)在世界范围内广泛流行, 是非常严重的公共卫生问题, 目前尚无有效的药物治疗措施。肝窦内皮细胞(LSECs)是肝脏中占比最大的非实质细胞, 但目前LSECs在NAFLD中发挥的作用尚不明确。现就近年LSECs在NAFLD中相关研究进展进行综述, 以期为后续的研究提供一定的参考。     

肝窦内皮细胞调控肝脏微环境影响肝纤维化的研究进展

肝窦内皮细胞不仅是血液和肝细胞进行物质交换的重要中介细胞,也是慢性肝损伤因素导致肝纤维化和肝硬化的重要肝非实质细胞。它主要通过与肝星状细胞、肝细胞、Kupffer细胞的相互作用和介导肝脏硬度、肝脏血管再生从而调控肝脏微循环,参与肝纤维化的发展。阐明这些机制,有助于探索肝纤维化治疗的新靶点和方案。     

肝窦内皮细胞在肝纤维化发生发展中的机制及相关治疗策略

肝窦内皮细胞不仅是保护肝脏免受损伤的第一道防线,也在慢性肝损伤导致的纤维化和肝硬化中伴有重要角色。它主要通过介导肝脏炎症反应、参与肝窦毛细血管化和血管再生、激活肝星状细胞、分泌多种促炎细胞因子、参与细胞外基质生成以及介导肝脏微循环障碍等参与肝纤维化。阐明这些机制,有助于探索肝纤维化治疗的新靶点和方案。     

肝血窦在内毒素致肝损伤中的作用

内毒素是革兰阴性菌细胞壁中的特有成分,又称脂多糖(LPS)。肝脏既是清除细菌和内毒素的场所,又是最易受损的器官。肝损伤最初发生在肝血窦。主要介绍了LPS对Kupffer细胞、肝窦内皮细胞、肝血窦中氧化/抗氧化平衡及肝脏血流的影响。认为肝血窦在LPS所造成的肝损伤中的作用不容忽视,研究其对防治LPS致肝损伤有重要意义。     

多种细胞在肝纤维化逆转中的作用

在多种慢性肝损伤病因的作用下,肝星状细胞(HSC)等活化为肌成纤维细胞(MFB),迁移至损伤部位并大量分泌细胞外基质(ECM),ECM在肝内过度沉积,从而形成肝纤维化。当肝损伤病因被移除或经过有效治疗后,肝纤维化可发生逆转。介绍了多种细胞参与肝纤维化的逆转过程,MFB通过自身衰老、凋亡、失活,在肝纤维化逆转中发挥关键作用;巨噬细胞通过加快ECM降解和诱导MFB衰老等发挥抗肝纤维化功能;肝窦内皮细胞通过维持其正常表型阻断并逆转肝纤维化;自然杀伤细胞杀伤处于活化早期的HSC和衰老的MFB,参与肝纤维化逆转。     

肝脏巨噬细胞及其在肝损伤中的作用

肝脏巨噬细胞来源和功能复杂,包括肝脏固有巨噬细胞和单核细胞来源的浸润巨噬细胞,在宿主防御机制及维持机体内环境稳定中起着重要作用,也是参与肝脏损伤和修复的主要细胞成分.解析不同来源肝脏巨噬细胞在不同病因导致肝损伤过程中表型分化、生物学作用的动态变化及其分子机制,对理解肝损伤的病理过程,探索以肝脏巨噬细胞为靶点预防和治疗肝损伤以及肝纤维化的方案具有重要意义.     

Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis,cirrhosis and hepatocellular carcinoma

Intercellular crosstalk among various liver cells plays an important role in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Capillarization of liver sinusoidal endothelial cells (LSECs) precedes fibrosis and accumulating evidence suggests that the crosstalk between LSECs and other liver cells is critical in the development and progression of liver fibrosis. LSECs dysfunction, a key event in the progression from fibrosis to cirrhosis, and subsequently obstruction of hepatic sinuses and increased intrahepatic vascular resistance (IHVR) contribute to development of portal hypertension (PHT) and cirrhosis. More importantly, immunosuppressive tumor microenvironment (TME), which is closely related to the crosstalk between LSECs and immune liver cells like CD8+ T cells, promotes advances tumorigenesis, especially HCC. However, the connections within the crosstalk between LSECs and other liver cells during the progression from liver fibrosis to cirrhosis to HCC have yet to be discussed.In this review, we first summarize the current knowledge of how different crosstalk between LSECs and other liver cells, including hepatocytes, hepatic stellate cells (HSCs), macrophoges, immune cells in liver and extra cellular matrix (ECM) contribute to the physiological function and the progrssion from liver fibrosis to cirrhosis, or even to HCC. Then we examine current treatment strategies for LSECs crosstalk in liver fibrosis, cirrhosis and HCC.     

Mechanisms balancing tolerance and immunity in the liver

The liver has a pivotal role in glucose, lipid and protein metabolism as well as in removal of toxins and waste products. A unique microanatomy and a network of resident scavenger cell populations specialized in endocytic uptake of antigens and macromolecules cooperatively mediate these salient hepatic functions together with parenchymal hepatocytes. Antigens taken up by hepatic scavenger cell populations, such as Kupffer cells, hepatic dendritic cells, stellate cells and liver sinusoidal endothelial cells (LSECs), can be (cross-)presented on MHC class I and II molecules, which leads to modulation of T cell immune functions. Among these cell populations, LSECs are endowed with the highest scavenger activity and are the most efficient cell population in cross-presenting soluble exogenous antigens to CD8 T cells. Together with their large number and the high cumulative surface area, LSECs represent the hepatic cell population that is best situated to interact with circulating T cells. Under physiological conditions, antigen-specific interaction of LSECs with CD8 T cells induces tolerance that is characterized by nonresponsiveness towards T cell receptor-mediated stimulation. In contrast to functional maturation of dendritic cells by activation through pattern recognition receptors, there is no such maturation in antigen-presenting LSECs, demonstrating that even under inflammatory conditions induction of CD8 T cell tolerance is preserved. However, upon viral infection of LSECs, a unique program of T cell differentiation into effector cytotoxic T cells is initiated that is independent of currently known costimulatory signals. These results highlight specific mechanisms operative in liver-resident antigen-presenting cells governing the local balance between tolerance and immunity.     

Nitric oxide from rat liver sinusoidal endothelial cells induces apoptosis in IFN gamma-sensitized CC531s colon carcinoma cells

BACKGROUND/AIMS: Investigation of apoptosis is pivotal in searching for mechanisms that eliminate colon cancer cells getting trapped in liver sinusoids at the time of surgical removal of the primary tumor. This study focuses on nitric oxide (NO), Fas/FasL and the involvement of interferon-gamma (IFNgamma) in liver sinusoidal endothelial cells (LSECs) and in the colon carcinoma cell line CC531s. METHODS: Apoptosis was quantified and visualized in vitro by specific DNA fragmentation, specific staining and electron microscopy. In vivo experiments were also conducted. RESULTS: In co-cultures of LSECs with CC531s, apoptosis of CC531s was observed only when they were pre-treated with IFNgamma, and was unaffected by blocking the Fas/FasL pathway. However, LSECs continuously produced NO, and apoptosis was inhibited by NO-inhibitors (NMMA and dexamethasone). When IFNgamma-sensitized CC531s were injected into rats, liver weight was lower, in contrast to control conditions where liver weight was higher. CONCLUSIONS: (i) LSECs induce apoptosis in IFNgamma-sensitized CC531s in vitro; (ii) LSECs express FasL; (iii) Fas on CC531s becomes active after IFNgamma-treatment; however, (iv) blocking the Fas/FasL pathway had no effect; (v) apoptosis was inhibited by NO-inhibitors; (vi) the immune system uses this IFNgamma-activated pathway to support LSECs in killing tumor cells.     

A novel mechanism of liver allograft rejection facilitated by antibodies to liver sinusoidal endothelial cells

Liver sinusoidal endothelial cells (LSECs) may be implicated in the induction of liver allograft rejections. We studied the clinical consequences of LSEC-reactive antibodies and their functional capacity in modulating T-cell responses during acute rejections. Pre- and posttransplant sera and T lymphocytes from 95 liver transplant patients were used in this study. LSECs were isolated from normal healthy liver. Binding of antibodies to LSECs was detected using flow cytometry. To study whether LSEC antibodies facilitated cell-mediated immunity, a mixed cell culture (MCC) assay was used. Cytokines in the supernatants of MCC were measured by enzyme-linked immunosorbent assay. Liver biopsy sections were stained to detect the deposition of immunoglobulins in LSECs during rejections. The 2-year patient survival was 86.3%. A significantly higher number of patients with rejections had LSEC antibodies (35/50; 70%) than those without rejections (8/45; 18%) (P < .0001). Purified fractions of LSEC antibodies induced the expression of the costimulatory molecule CD86 on LSECs. A significantly higher number of patients with LSEC antibodies and rejections had an increased proliferation of T cells and markedly decreased levels of transforming growth factor beta (TGF-beta) in the MCC than those without antibodies and rejections (P < .0001, P < .0001, respectively). Deposition of antibodies in LSECs during rejection episodes was observed in the biopsies of patients with LSEC antibodies but not in those without LSEC antibodies. In conclusion, antibodies to LSECs may facilitate acute liver allograft rejections by down-regulating the immune modulating cytokine TGF-beta and thus up-regulating alloreactive T-cell proliferation.     

Liver sinusoidal endothelial and biliary cell repopulation following irradiation and partial hepatectomy

AIM: To investigate whether irradiation (IR) and partial hepatectomy (PH) may prepare the host liver for nonparenchymal cell (NPC) transplantation.METHODS: Livers of dipeptidyl peptidase(DPP)-deficient rats were pre-conditioned with external beam IR (25 Gy) delivered to two-thirds of the right liver lobules followed by a one-third PH of the untreated lob-ule. DPP-positive liver cells (NPC preparations enriched for liver sinusoidal endothelial cells (LSECs) and hepatocytes) were transplanted via the spleen i...     

Liver immunity,autoimmunity, and inborn errors of immunity

The liver is the front line organ of the immune system.The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens.This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens,such as food antigens or pathogens.As an immune active organ,the liver functions as a gatekeeping barrier from the outside world,and it can create...     

Hepatic disposal of advanced glycation end products during maturation and aging

Aging is characterized by progressive loss of metabolic and biochemical functions and accumulation of metabolic by-products, including advanced glycation end products (AGEs), which are observed in several pathological conditions. A number of waste macromolecules, including AGEs are taken up from the circulation by endocytosis mainly into liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs). However, AGEs still accumulate in different tissues with aging, despite the presence of this clearance mechanism. The aim of the present study was to determine whether the efficiency of LSECs and KCs for disposal of AGEs changes through aging.     

Sinusoidal endothelial cell repopulation following ischemia/reperfusion injury in rat liver transplantation

We evaluated the kinetics by which rat liver sinusoidal endothelial cells (LSECs) are repopulated in the reperfused transplanted liver after 18 hours of cold ischemic storage. We found that the majority of LSECs in livers cold-stored for 18 hours in University of Wisconsin solution are seriously compromised and often are retracted before transplantation. Sinusoids rapidly re-endothelialize within 48 hours of transplantation, and repopulation is coincident with up-regulation of hepatocyte vascular endothelial growth factor expression and vascular endothelial growth factor receptor-2 expression on large vessel endothelial cells and repopulating LSECs. Although re-endothelialization occurs rapidly, we show here, using several high-resolution imaging techniques and 2 different rat liver transplantation models, that engraftment of bone marrow-derived cells into functioning LSECs is routinely between 1% and 5%. CONCLUSION: Bone marrow plays a measurable but surprisingly limited role in the rapid repopulation and functional engraftment of bone marrow-derived LSECs after cold ischemia and warm reperfusion.