Structural and functional aspects of the liver and liver sinusoidal cells in relation to colon carcinoma metastasis

Nowadays, liver metastasis remains difficult to cure. When tumor cells escape and arrive in the liver sinusoids, they encounter the local defense mechanism specific to the liver. The sinusoidal cells have been widely described in physiologic conditions and in relation to metastasis during the past 30 years. This paper provides an "overview" of how these cells function in health and in diseases such as liver metastasis.     

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。     

精密肝切片技术在肝纤维化研究中的应用研究进展

精密肝切片(precision-cut liver slice,PCLS)技术是一种介于器官与细胞水平间的肝脏体外实验技术,由于其切片技术相对简单,无需使用胶原酶,且能够较完整保存正常组织结构、细胞联系及细胞极性(polantyofhepatic cell),因而能最大限度地模拟在体状态,目前已广泛应用于药物(或毒物)代谢、氧化应激、种属间药物作用差异等方面的研究[1-2].近年来,PCLS技术因其在研究肝星状细胞(HSC)激活和肝纤维化方面的潜在应用价值而受到愈来愈广泛地关注.本文旨在介绍这一新技术的主要特点及其在肝纤维化方面的主要研究进展.     

肝血窦内皮细胞在非酒精性脂肪性肝病发展中的作用

非酒精性脂肪性肝病(NAFLD)是以肝脏脂肪变、炎症和纤维化为主要表现的临床代谢综合征,日渐成为严重影响公众健康的常见慢性肝病。肝血窦内皮细胞(LSEC)是肝脏组织特化的血管内皮细胞,作为一道重要的血管屏障,其对肝脏细胞吸收和代谢源自肠道血液中的营养与物质成分发挥重要调节作用。介绍了NAFLD发生发展进程中LSEC毛细血管化、血管功能障碍及其参与调控肝脏炎症、血管生成、肝纤维化的研究进展。     

肝干细胞移植治疗肝脏疾病的研究进展

肝干细胞移植治疗急、慢性肝衰竭为治疗肝衰竭开辟了一个新途径。采用肝干细胞移植治疗肝衰竭,移植的肝干细胞可直接参与修复肝组织或帮助肝脏渡过危险期,为后期肝移植赢得时间。近年来,肝干细胞移植研究取得较大的进展,为这一技术从实验室向临床过渡奠定了基础。笔者就肝干细胞移植治疗肝脏疾病的研究进展进行简要综述。     

骨髓间充质干细胞向肝（样）细胞的分化及其在肝脏疾病的应用

骨髓间充质干细胞在肝脏病理条件或体外诱导分化为有功能的肝（样）细胞以及对受损肝脏的修复作用是目前研究的热点。本文就骨髓间充质干细胞分化潜能及其可能的机制、免疫学特性以及在肝脏疾病的应用研究作系统的综述。     

肝脏自然杀伤细胞在慢性肝病中的作用

肝脏自然杀伤细胞（NK）是一种与外周血NK细胞不同的肝脏免疫细胞。近年来研究表明肝脏NK细胞在各种慢性肝脏疾病中起重要作用。包括对抑制病毒感染和肿瘤细胞生长,对抗肝纤维化均有益处,但同时其又刺激肝损伤和抑制肝再生（肝细胞增殖）。本文就肝脏NK细胞的特征、功能以及在各种常见慢性肝病中作用进展作一综述。     

肝纤维化形成中细胞学机制的研究进展

一、肌成纤维细胞:目前认为肌成纤维细胞主要来自激活的肝星状细胞(hepatic stellate cell,HSC)及门静脉成纤维细胞(portal fibroblast,PF),也可从骨髓源性细胞分化而来.也有报道称肝细胞及胆管上皮细胞可以通过上皮-间质转化(epithelial-to-mesenchymal transition,EMT)而来,然而仍存在争议.     

肝脏非实质细胞在肝脏缺血再灌注损伤中的作用

肝脏非实质细胞在肝脏中发挥着非常重要的作用。回顾近几年关于非实质肝细胞,如Kupffer细胞、肝窦内皮细胞、肝星状细胞、树突状细胞等在肝脏缺血再灌注损伤(HIRI)中的作用。分析表明肝脏非实质细胞在HIRI过程中扮演着非常重要的角色,能通过各种途径最终加重或者减轻HIRI。     

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。     

Stem and progenitor cell systems in liver development and regeneration

The liver comprises two stem/progenitor cell systems: fetal and adult liver stem/progenitor cells. Fetal hepatic progenitor cells, derived from foregut endoderm, differentiate into mature hepatocytes and cholangiocytes during liver development. Adult hepatic progenitor cells contribute to regeneration after severe and chronic liver injuries. However, the characteristics of these somatic hepatic stem/progenitor cells remain unknown. Culture systems that can be used to analyze these cells were recently established and hepatic stem/progenitor cell‐specific surface markers including delta‐like 1 homolog (DLK), cluster of differentiation (CD) 13, CD133, and LIV2 were identified. Cells purified using antibodies against these markers proliferate for an extended period and differentiate into mature cells both in vitro and in vivo. Methods to force the differentiation of human embryonic stem and induced pluripotent stem (iPS) cells into hepatic progenitor cells have been recently established. We demonstrated that the CD13⁺CD133⁺ fraction of human iPS‐derived cells contained numerous hepatic progenitor‐like cells. These analyses of hepatic stem/progenitor cells derived from somatic tissues and pluripotent stem cells will contribute to the development of new therapies for severe liver diseases.     

肝干细胞在肝病治疗中的应用

肝病是危害我国人民健康的严重疾病，如何治疗肝病是广大研究人员最为关注的课题。近年来，全球掀起了有关干细胞的研究热潮，为疾病的治疗提供崭新思路。其中造血干细胞移植治疗血液系统疾病较为成熟，并且自体骨髓干细胞冶疗心肌梗死，间充质干细胞治疗造血功能低下、帕金森氏病，以及构建组织工程骨，这些临床应用都收到了良好效果。这为肝干细胞在肝病治疗中的应用提供了新的契机。     

髓系来源的抑制细胞在肝病发病中的作用研究进展*

髓系来源的抑制细胞来源于骨髓祖细胞和未成熟的髓系细胞。近年来的研究表明,该细胞参与调节多种肝脏疾病的病理变化。本文系统地归纳了髓系来源的抑制细胞的历史、分群、作用机制和当前该细胞在各种肝病发病中的免疫调控作用及其与疾病进展的关系。     

The ultrastructure of the liver reticulo-endothelial cells in diabetics

Summary The following utrastructural modifications were noticed in a group of 28 diabetic and 2 normal individuals: a) a rather patchy endothelial proliferation with b) frequent hypertrophy which occasionally arrives to obliterate the sinusoidal lumen; c) increased number of cytoplasmic organelles and lysosomes, big and irregular nuclei; d) numerous and various in shape pseudopodic cellular prolongations; e) reduced number of pynocytoticcaveolae intracellulares; f) a certain dilatation of the rough ergastoplasmic reticulum. Comparison was made with the changes noticed in the same patient in the peripheric capillaries (biopsies of the calf) and a functional study of the reticuloendothelial system of the liver (nicotinic acid i.v. test) was carried out. The existence of the diabetic microangiopathy in the liver is discussed as part of the known diabetic vascular changes described in the peripheric capillaries and the possibility of micro-ischaemic disturbances in the liver itself is suggested.

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Zusammenfassung Es wurde die ultramikroskopische Struktur der Leberepithelzellen bei bioptischem Material von 28 Diabetikern und 2 Gesunden untersucht: a) ziemlich ueberschiessende Proliferation der endothelialen Zellen; b) sehr haeufige Hypertrophie; Zelldurchmesser der etliche Male groesser als der normale ist; daher des oefteren Sinusoidal-Obliteration; c) Zunahme der Anzahl der zytoplasmatischen kleinen Organe sowie der Lysosome; grosse und sehr unregelmaessige Kerne; d) zahlreiche und polymorphe Microvilli; e) Reduktion der Anzahl der pinozytotischencaveolae intracellulares; f) eine gewisse Erweiterung des rauhen ergastoplasmatischen Reticulums. Es wurde keine Korrelation, weder zur Schwere und Dauer des Diabetes, noch zum Alter und Geschlecht des Patienten festgestellt. Ferner wurde ein Vergleich mit den Veraenderungen der peripheren Kapillaren desselben Patienten (Biopsie der Wade) angestellt und ausserdem untersuchte man den funktionellen Zustand des Retikulo-Endothelial-Systems der Leber (Nikotinsaeure-Test). Das Dasein der diabetischen Leber-Mikroangiopathie wird im Sinne der bekannten und beschriebenen diabetischen Gefaess-Schaeden bei den peripheren Kapillaren diskutiert und man bespricht die Moeglichkeit von mikroischaemischen Stoerungen in der Leber selbst.

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Resumen Ha sido estudiada la estructura ultramicroscópica de las células endoteliales hepáticas sobre material de biopsia extraído a 28 diabéticos y a 2 sujetos sanos: a) presencia de proliferaciones de las células endoteliales más bien imponentes; b) frecuentísima hipertrofia, hasta varias veces en diámetro celular normal, provocando frecuentemente la obliteración de la luz sinusoidal; c) aumento del número de los pequeños organos citoplasmáticos y de los lisosomas, nucleos grandes y muy irregulares; d) microvellosidades numerosas y polimorfas; e) reducción del número de lascaveolae intracellulares pinocitóticas; f) cierta dilatación del retículo ergastoplásmico áspero. No han sido apreciadas correlaciones con la gravedad y la duración de la diábetes ni con la edad y el sexo del enfermo. Ha sido efectuada una comparación con las modificaciones observadas en los capilares periféricos del mismo paciente (biopsias de la pantorrila) y el estudio funcional del sistema retículo-endotelial del hígado (test del ácido nicotínico). La existencia de la microangiopatía diabética hepática se discute como parte de las bien conocidas alteraciones vasculares diabéticas descritas en los capilares periféricos, y se vislumbra la posibilidad de trastornos microisquémicos en el mismo hígado.

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Resume On a étudié la structure ultramicroscopique des cellules endothéliales hépatiques sur tissue bioptique de 28 diabétiques et de 2 sujets sains: a) presence d'une massive prolifération des cellules endothéliales; b) très fréquente hypertrophie, jusqu'à plusieures fois le diamètre cellulaire normale, telle qui porte souvent à l'oblitération du lumen sinusoïdal; c) augmentation du nombre des organules cytoplasmatiques et des lysosomes, noyaux gros et très irréguliers; d) plusieurs et polimorphes microvillosités; e) réduction du nombre descaveolae intracellulares pynocitotiques; f) certaine dilatation du réticulum ergastoplasmique rugueux. On n'a pas observé des corrélations avec la gravité et la durée du diabète, l'âge et le sexe du malade. L'A. a effectué une comparaison avec les modifications observées dans les capillaires périphériques du même sujet (biopsie du mollet) et l'étude fonctionel du système réticulo-endothéliale du foie (test à l'acide nicotinique). L'existence de la microangiopathie diabétique hépatique est considérée comme partie des bien connues altérations vasculaires diabétiques déscrites dans les capillaires périphériques et on suggère la possibilité des altérations microischémiques dans le foie.

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Riassunto E' stata studiata la struttura ultramicroscopica delle cellule endoteliali epatiche su materiale bioptico ottenuto da 28 diabetici e 2 soggetti sani: a) presenza di proliferazione delle cellule endoteliali piuttosto imponente; b) frequentissima ipertrofia, fino a diverse volte il diametro cellulare normale, tale da dare frequentemente l'obliterazione del lume sinusoidale; c) aumento del numero degli organuli citoplasmatici e dei lisosomi, nuclei grossi e molto irregolari; d) microvilli numerosi e polimorfi; e) riduzione nel numero dellecaveolae intracellulares pinocitotiche; f) talora una certa dilatazione del reticolo ergastoplasmico ruvido. Non sono state rilevate correlazioni con la gravità e la durata del diabete nè con l'età ed il sesso dell'ammalato. E' stato effettuato un confronto con le modificazioni osservate nei capillari periferici dello stesso paziente (biopsie del polpaccio) e lo studio funzionale del sistema reticolo-endoteliale del fegato (test all'acido nicotinico i.v.). L'esistenza della microangiopatia diabetica epatica viene discussa come parte delle note alterazioni vascolari diabetiche, descritte nei capillari periferici, e viene suggerita la possibilità di disturbi micro-ischemici nel fegato stesso.

     

Localization and regulation of aromatase liver receptor homologue-1 in the developing rat testis

The enzyme aromatase converts androgens to estrogens, which have recently been postulated to be essential for testicular development and fertility. Understanding the mechanisms that regulate aromatase activity in the testis may therefore have implications for treatment of male infertility. Aromatase is encoded by the CYP19 gene, which uses multiple tissue-specific alternative promoters. In the testis, the proximal promoter PII drives aromatase expression. PII activity requires a nuclear receptor half-site, CAAGGTCA, to which two orphan receptors; SF-1 and LRH-1, have been shown to bind in vitro. The aim of this study was to investigate expression of aromatase and LRH-1 in the developing rat testis and define the ability of LRH-1 to induce aromatase expression in the testicular cells where both are expressed. We show that aromatase and LRH-1 are present throughout all stages of development of the rat testis, although the sites and levels of expression vary. The pattern of LRH-1 expression was broadly similar to that of aromatase. In adult animals higher levels of expression were observed in Leydig and germ cells. Over-expression of LRH-1 in primary rat Leydig and germ cells by adenoviral infection strongly increased endogenous aromatase mRNA levels, demonstrating the ability of LRH-1 to stimulate aromatase expression in vivo. We also observed binding of endogenous LRH-1 to the aromatase promoter II by chromatin immunoprecipitation. These data provide evidence that LRH-1 plays an important role in the regulation of testicular aromatase expression, and implicate LRH-1 as a regulator of rat spermatogenesis, in which estrogens are emerging as important mediators.     

干细胞治疗在肝病中的应用

近年来,干细胞治疗肝病受到广泛重视。在急性肝衰竭、终末期慢性肝病、遗传代谢性肝病等均有应用。干细胞有强大的自我更新能力。可分为肝细胞来源的干细胞和非肝细胞来源的干细胞。干细胞可向肝细胞或类肝细胞分化。