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首页> 外文期刊>The journal of clinical investigation >Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes
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Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes

机译：野生型供体肝细胞表达突变型人α1-抗胰蛋白酶的转基因小鼠中的自发性肝细胞繁殖

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α1-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 α1-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导致肝病和肺气肿的遗传病。该蛋白质由肝脏合成，其正常功能是抑制嗜中性白细胞弹性蛋白酶，该蛋白酶可降解肺部结缔组织。在该疾病的经典形式中，突变型α1-抗胰蛋白酶（AAT-Z）的分泌效率低下导致其在肝细胞内积累并降低了蛋白酶抑制剂的活性，从而导致肝损伤和肺气肿。因为突变蛋白的积累会增加肝细胞的压力，所以我们使用表达人AAT-Z的转基因小鼠调查了表达野生型AAT的移植肝细胞相对于表达AAT-Z的肝细胞是否具有竞争优势。野生型供体肝细胞替代了突变宿主肝细胞的20％–98％，并且通过注射表达肝细胞生长因子的腺载体促进了种群的再增殖。即使没有严重的肝损伤，在表达AAT-Z的小鼠中也会发生带有移植肝细胞的自发性肝细胞繁殖。供体细胞替代了含小球的细胞和无小球的细胞，表明两种类型的宿主肝细胞均相对于野生型肝细胞显示出受损的增殖。这些结果表明，野生型肝细胞移植可以治疗AAT-Z肝病，并且可以为蛋白质替代提供替代疗法，以治疗AAT-ZZ个体的肺气肿。

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