Department of Pathology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, United States.
Department of Surgery, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, United States.
J Hepatol. 2019 Jun;70(6):1170-1179. doi: 10.1016/j.jhep.2019.01.010. Epub 2019 Jan 14.
BACKGROUND & AIMS: Inherited abnormalities in apolipoprotein E (ApoE) or low-density lipoprotein receptor (LDLR) function result in early onset cardiovascular disease and death. Currently, the only curative therapy available is liver transplantation. Hepatocyte transplantation is a potential alternative; however, physiological levels of hepatocyte engraftment and repopulation require transplanted cells to have a competitive proliferative advantage of over host hepatocytes. Herein, we aimed to test the efficacy and safety of a novel preparative regimen for hepatocyte transplantation.
Herein, we used an ApoE-deficient mouse model to test the efficacy of a new regimen for hepatocyte transplantation. We used image-guided external-beam hepatic irradiation targeting the median and right lobes of the liver to enhance cell transplant engraftment. This was combined with administration of the hepatic mitogen GC-1, a thyroid hormone receptor-β agonist mimetic, which was used to promote repopulation.
The non-invasive preparative regimen of hepatic irradiation and GC-1 was well-tolerated in ApoE mice. This regimen led to robust liver repopulation by transplanted hepatocytes, which was associated with significant reductions in serum cholesterol levels after transplantation. Additionally, in mice receiving this regimen, ApoE was detected in the circulation 4 weeks after treatment and did not induce an immunological response. Importantly, the normalization of serum cholesterol prevented the formation of atherosclerotic plaques in this model.
Significant hepatic repopulation and the cure of dyslipidemia in this model, using a novel and well-tolerated preparative regimen, demonstrate the clinical potential of applying this method to the treatment of inherited metabolic diseases of the liver.
Hepatocyte transplantation is a promising alternative to liver transplantation for the treatment of liver diseases. However, it is inefficient, as restricted growth of transplanted cells in the liver limits its therapeutic benefits. Preparative treatments improve the efficiency of this procedure, but no clinically-feasible options are currently available. In this study we develop a novel well-tolerated preparative treatment to improve growth of cells in the liver and then demonstrate that this treatment completely cures an inherited lipid disorder in a mouse model.
载脂蛋白 E（ApoE）或低密度脂蛋白受体（LDLR）功能的遗传异常导致心血管疾病和早逝。目前，唯一可用的治愈疗法是肝移植。肝细胞移植是一种潜在的替代方法；然而，需要移植细胞具有比宿主肝细胞更具竞争力的增殖优势，才能实现肝细胞的生理性植入和再增殖。在此，我们旨在测试肝细胞移植的新方案的疗效和安全性。
在此，我们使用 ApoE 缺陷型小鼠模型来测试肝细胞移植的新方案的疗效。我们使用图像引导的外部束肝脏照射靶向肝脏的中肝叶和右肝叶，以增强细胞移植的植入。这与肝有丝分裂原 GC-1 的给药相结合，GC-1 是一种甲状腺激素受体-β激动剂模拟物，用于促进再增殖。
在 ApoE 小鼠中，肝照射和 GC-1 的非侵入性预处理方案耐受良好。该方案导致移植的肝细胞在肝脏中大量再增殖，这与移植后血清胆固醇水平的显著降低有关。此外，在接受该方案的小鼠中，ApoE 在治疗后 4 周在循环中被检测到，并且没有引起免疫反应。重要的是，这种胆固醇水平的正常化阻止了该模型中动脉粥样硬化斑块的形成。
使用新型且耐受良好的预处理方案，在该模型中观察到显著的肝再增殖和血脂异常的治愈，表明该方法在治疗肝脏遗传性代谢疾病方面具有临床潜力。
肝细胞移植是治疗肝脏疾病的肝移植的一种有前途的替代方法。然而，它的效率较低，因为移植细胞在肝脏中的生长受限限制了其治疗效果。预处理可以提高该程序的效率，但目前尚无可行的临床选择。在这项研究中，我们开发了一种新型的、耐受良好的预处理方法来改善细胞在肝脏中的生长，然后证明这种治疗方法可以完全治愈小鼠模型中的一种遗传性脂质紊乱。
