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Inventory of Artificial Liver Support based on the mixed culture system of Hepatocytes with Ito cells

基于肝细胞与伊藤细胞混合培养体系的人工肝支持盘点

基本信息

批准号：
11308036
负责人：
ISHII Hiromasa
金额：
$ 22.66万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

Cell- cell interactions are important in embryogenesis, in adult physiology and pathophysiology of many disease processes. Co-cultivation of parenchymal and mesenchymal cells has been widely utilized as a paradigm for the study of cell-cell interactions in vitro. In addition, co-cultures of two cell types provide highly functional tissue constructs for use in therapeutic or investigational applications. In this study, we utilize micro fabrication techniques to localize both cell populations in patterned configulations on rigid substrates. We were able to control the level of homotypic interaction in cultures of single cell type and the degree of heterotypic contact in co-culture over a wide range. We have experimentally shown that stellate cells numbers and increased heterotipic cell-cell interactions influences hepatocellular functions. Organs are composed of many individual cell types and together responsible for orchestrating tissue functions. We could mimic liver function in vitro … More and utilize this sytem to elucidate fundamental factors of liver development. We monitored liver -specific functions by urea synthesis and albumin secretion, varied 2-fold with increasing heterotipic cell-cell interactions. Urea is a marker of metabolic function and albumin secretion is a marker of synthetic function. We also investigated lipid metabolism and P450 enzymatic detoxification activity. All data indicated that increasing heterotipic cell-cell interactions contributed maintaining liver specific functions. Moreover we could induced some hepatocyte specific protein expression in ES cells when we co-cultivate ES cells in this system. These evidence indicate that this approach will allow further elucidation of the complex interplay betweentwo cell types as they form a functional model tissue in vitro or as they interact in vivo to form functional organ. Although further investigations are necessary to develop artificial liver for clinical use, this study has clearly shown that appropriate co-clutivation method is numers of advantage over the other approaches. Less

细胞间的相互作用在胚胎发育、成体生理学和许多疾病过程的病理生理学中都是重要的。骨髓间充质细胞与实质细胞共培养已被广泛应用于细胞与细胞相互作用的体外研究。此外，两种细胞类型的共培养提供了用于治疗或研究应用的高功能组织结构。在这项研究中，我们利用微制造技术将两个细胞群体定位在刚性衬底上的图案化配置中。我们能够在很大范围内控制单细胞类型培养中同型相互作用的水平和共培养中异型接触的程度。我们的实验表明，星状细胞的数量和增加的异质性细胞-细胞相互作用影响肝细胞的功能。器官由许多单独的细胞类型组成，共同负责协调组织的功能。我们可以在体外…中模拟肝功能更多地利用该系统阐明肝脏发育的基本因素。我们通过尿素合成和白蛋白分泌来监测肝脏的特异性功能，随着异质性细胞-细胞相互作用的增加而变化2倍。尿素是代谢功能的标志，白蛋白分泌是合成功能的标志。我们还研究了脂类代谢和P450酶解毒活性。所有数据都表明，异质性细胞-细胞相互作用的增加有助于维持肝脏的特异性功能。此外，当我们在该体系中与ES细胞共培养时，我们还可以在ES细胞中诱导一些肝细胞特异性蛋白的表达。这些证据表明，这种方法将进一步阐明两种细胞类型在体外形成功能模型组织或在体内相互作用形成功能器官时的复杂相互作用。虽然人工肝的临床应用还需要进一步的研究，但这项研究已经清楚地表明，适当的共凝集方法比其他方法具有更多的优势。较少