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Research for the formation of hepatic organoids by using human hepatic progenitor cells and the model of artificial liver device incorporated with human hepatic organoids

利用人肝祖细胞形成肝类器官及结合人肝类器官的人工肝装置模型研究

基本信息

批准号：
17390353
负责人：
MITAKA Toshihiro
金额：
$ 10.82万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

We have reported that CD44 is specifically expressed in rat small hepatocytes and that CD44^+ hepatocytes transiently appear in injured rat livers. Using a specific antibody, we sorted CD44^+ cells from galactosamine-treated rat livers and cultured them. The phenotypes and gene expression of the cells were similar to those of cultured SHs and the ^+ cells could differentiate into hepatocytes (J Hepatol, 2006). In addition, some Thy1^+ cells that appeared in the galactosamine-treated livers could differentiate into + SHs and mature into hepatocytes. When the Thyl+ and CD44^+ cells were transplanted into livers treated with retrorsine/PH, they could survive and proliferate to form hepatic foci in the recipient livers. Furthermore, when cultured SHs were transplanted into congenic rat livers treated with radiation/PH, the cells migrated into hepatic trabecules and the liver was partially repopulated by the donor cells (Liver Transplant, 2006). Rat SHs cultured in hyaluronic acid (HA ; ligand for CD44)-coated dishes and serum-free medium could selectively proliferate with hepatic functions (Nature Protocols, 2007) and this method could be applied for the isolation of human SHs from normal liver tissues, which were surgically resected from patients with informed consent. The number of human SHs increased about 100-fold within 3 weeks and the cells showed hepatic characteristics such as albumin secretion (Cell Transplant, 2008). Furthermore, we found that the proliferation of rat SHs was enhanced by follistatin produced by SHs to inhibit the action of activin A, which is secreted by mature hepatocytes. On the other hand, we succeeded in reconstructing functional hepatic tissues by stacking up two-dimensional tissues composed of rat SHs (FASEB J, 2006). In addition, we could culture normal rat biliary epithelial cells for a long term and reconstruct functional bile ductules between collagen gels (Am J Pathol, 2008).

我们已经报道了CD 44在大鼠小肝细胞中特异性表达，并且CD 44 ^+肝细胞在损伤的大鼠肝脏中短暂出现。我们用特异性抗体从半乳糖胺处理过的大鼠肝脏中分选出CD 44 ^+细胞并进行培养。细胞的表型和基因表达与培养的SH相似，并且^+细胞可以分化为肝细胞（J Hepatol，2006）。此外，半乳糖胺处理的肝脏中出现的一些Thy 1 ^+细胞可分化为+SH并成熟为肝细胞。将Thyl+和CD 44 ^+细胞移植到经反曲马新/PH处理的肝脏中，它们可以在受体肝脏中存活并增殖形成肝灶。此外，当将培养的SH移植到用辐射/PH处理的同类大鼠肝脏中时，细胞迁移到肝小梁中，并且肝脏被供体细胞部分地重新填充（Liver Transplant，2006）。在透明质酸（HA ; CD 44的配体）包被的培养皿和无血清培养基中培养的大鼠SH可以选择性地随着肝功能增殖（Nature Protocols，2007），并且该方法可以应用于从正常肝组织中分离人SH，所述正常肝组织是在知情同意的情况下从患者手术切除的。人SH的数量在3周内增加了约100倍，并且细胞显示出肝脏特征，例如白蛋白分泌（Cell Transplant，2008）。此外，我们发现，促进大鼠SH细胞的增殖卵泡抑素产生的SH抑制激活素A，这是由成熟的肝细胞分泌的行动。另一方面，我们通过堆叠由大鼠SH组成的二维组织成功地重建了功能性肝组织（FASEB J，2006）。此外，我们可以长期培养正常大鼠胆管上皮细胞，并在胶原凝胶之间重建功能性胆管（Am J Pathol，2008）。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reconstruction of 3D liver-like structures by stacking up layers of rat small hepatocytes,

通过堆叠大鼠小肝细胞层重建 3D 肝脏样结构，

DOI：
发表时间：
2005
期刊：
Proc The second Japan-Switzerland workshop on biomechanics
影响因子：
0
作者：
T.Sugawara;M.M.Matsushita;Tanishita K et al.
通讯作者：
Tanishita K et al.

Proliferation of Hepatocyte Progenitor Cells Isolated from Adult Human Livers in Serum-Free Medium

DOI：
10.3727/096368908787236666
发表时间：
2008-10
期刊：
Cell Transplantation
影响因子：
3.3
作者：
K. Sasaki;J. Kon;T. Mizuguchi;Qijie Chen;Hidekazu Ooe;H. Oshima;K. Hirata;T. Mitaka
通讯作者：
K. Sasaki;J. Kon;T. Mizuguchi;Qijie Chen;Hidekazu Ooe;H. Oshima;K. Hirata;T. Mitaka

Selective proliferation of rat hepatocyte progenitor cells in serum-free culture