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首页> 外文期刊>The Journal of Clinical Investigation: The Official Journal of the American Society for Clinical Investigation >Spontaneous hepatic repopulation in transgenic mice expressing mutant human alpha1-antitrypsin by wild-type donor hepatocytes.
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Spontaneous hepatic repopulation in transgenic mice expressing mutant human alpha1-antitrypsin by wild-type donor hepatocytes.

机译：野生型供体肝细胞在表达突变人α1-抗胰蛋白酶的转基因小鼠中自发的肝脏再繁殖。

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alpha1-Antitrypsin deficiency is an inherited condition that causes liver disease and emphysema. The normal function of this protein, which is synthesized by the liver, is to inhibit neutrophil elastase, a protease that degrades connective tissue of the lung. In the classical form of the disease, inefficient secretion of a mutant alpha1-antitrypsin protein (AAT-Z) results in its accumulation within hepatocytes and reduced protease inhibitor activity, resulting in liver injury and pulmonary emphysema. Because mutant protein accumulation increases hepatocyte cell stress, we investigated whether transplanted hepatocytes expressing wild-type AAT might have a competitive advantage relative to AAT-Z-expressing hepatocytes, using transgenic mice expressing human AAT-Z. Wild-type donor hepatocytes replaced 20-98 of mutant host hepatocytes, and repopulation was accelerated by injection of an adenovector expressing hepatocyte growth factor. Spontaneous hepatic repopulation with engrafted hepatocytes occurred in the AAT-Z-expressing mice even in the absence of severe liver injury. Donor cells replaced both globule-containing and globule-devoid cells, indicating that both types of host hepatocytes display impaired proliferation relative to wild-type hepatocytes. These results suggest that wild-type hepatocyte transplantation may be therapeutic for AAT-Z liver disease and may provide an alternative to protein replacement for treating emphysema in AAT-ZZ individuals.
机译：α1-抗胰蛋白酶缺乏症是一种导致肝病和肺气肿的遗传性疾病。这种由肝脏合成的蛋白质的正常功能是抑制中性粒细胞弹性蛋白酶，这是一种降解肺结缔组织的蛋白酶。在该疾病的经典形式中，突变 α1-抗胰蛋白酶 （AAT-Z） 的低效分泌导致其在肝细胞内积累并降低蛋白酶抑制剂活性，从而导致肝损伤和肺气肿。由于突变蛋白积累会增加肝细胞应激，因此我们使用表达人AAT-Z的转基因小鼠研究了表达野生型AAT的移植肝细胞是否相对于表达AAT-Z的肝细胞具有竞争优势。野生型供体肝细胞取代了20%-98%的突变宿主肝细胞，通过注射表达肝细胞生长因子的腺载体加速了重新繁殖。即使在没有严重肝损伤的情况下，在表达AAT-Z的小鼠中也发生了移植肝细胞的自发肝脏再繁殖。供体细胞取代了含小球细胞和无小球细胞，表明两种类型的宿主肝细胞相对于野生型肝细胞都表现出增殖受损。这些结果表明，野生型肝细胞移植可能治疗AAT-Z肝病，并可能为治疗AAT-ZZ个体的肺气肿提供蛋白质替代的替代方法。

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