Regenerative and therapeutic effects of heparin-binding epidermal growth factor-like growth factor on diabetes by gene transduction through retrograde pancreatic duct injection of adenovirus vector
Regenerative and therapeutic effects of heparin-binding epidermal growth factor-like growth factor on diabetes by gene transduction through retrograde pancreatic duct injection of adenovirus vector
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DOI：
10.1097/01.mpa.0000163177.59920.f8
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发表时间：
2005-07-01
期刊：
影响因子：
2.9
通讯作者：
Miyagawa, J
中科院分区：
文献类型：
--
作者：
Kozawa, J;Tokui, Y;Miyagawa, J
目的：在成年胰腺中，存在于导管衬里中的预先存在的β细胞、干细胞和内分泌祖细胞被认为是β细胞再生的重要来源。表皮生长因子（EGF）家族的成员，肝素结合（HB）-EGF，可以促进这一过程。我们研究是否HB-EGF基因转导到导管细胞可以促进β-cell regeneration.Methods：我们管理的HB-EGF腺病毒载体构建的雄性癌症研究所小鼠通过逆行注射通过胰管。结果：免疫组化和组织形态计量学分析显示，实验组大鼠胆管细胞分化为胰岛素阳性细胞，β细胞5-溴-2-脱氧尿苷标记指数明显增加。β-细胞质量也增加，糖尿病小鼠的葡萄糖耐量在注射后12周得到改善。使用培养的胰腺导管细胞，我们证实，HB-EGF基因转导诱导胰岛素基因表达和胰岛素生产由这些cells.Conclusions：这些结果表明，HB-EGF基因转导到成人胰腺导管细胞不仅促进增殖的预先存在的β细胞，但也导致β细胞分化的导管细胞，并由此产生的β细胞质量的增加，提高葡萄糖耐量。
Objectives: In the adult pancreas, pre-existing beta cells, stem cells, and endocrine progenitor cells residing in the duct lining are considered important sources for beta-cell regeneration. A member of the epidermal growth factor (EGF) family, heparin binding (HB)-EGF, may promote this process. We examined whether HB-EGF gene transduction into duct cells could promote beta-cell regeneration.Methods: We administered an HB-EGF adenovirus vector construct to male Institute of Cancer Research mice by retrograde injection through the pancreatic duct. We also performed HB-EGF gene transduction into cultured duct cells.Results: On immunohistochemical and histomorphometric analysis of the experimental group, insulin-positive cells differentiated from duct cells, and the 5-bromo-2-deoxyuridine labeling index of beta cells was significantly increased. beta-cell mass was also increased, and the glucose tolerance of diabetic mice was improved at 12 weeks after injection. Using cultured pancreatic duct cells, we confirmed that HB-EGF gene transduction induced both insulin gene expression and insulin production by these cells.Conclusions: These results indicate that HB-EGF gene transduction into adult pancreatic duct cells not only promotes the proliferation of pre-existing beta cells but also leads to beta-cell differentiation from duct cells, and the resulting increase in beta-cell mass improves glucose tolerance.