Feasibility of hepatocyte transplantation-based therapies for primary hyperoxalurias
Feasibility of hepatocyte transplantation-based therapies for primary hyperoxalurias
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DOI：
10.1159/000085408
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发表时间：
2005-01-01
影响因子：
4.2
通讯作者：
Roy-Chowdhury, J
中科院分区：
文献类型：
--
作者：
Guha, C;Yamanouchi, K;Roy-Chowdhury, J
原发性高草酸血症（PHs）是由肝细胞过量产生草酸引起的疾病。大多数小灵通患者会发生肾钙质沉着症和肾功能衰竭。肝肾联合移植通常被用作小灵通的最终治疗方法，但由于移植时体内草酸盐负荷很大，该手术并不总是成功的。由于所有肝细胞都过量产生草酸盐，部分肝脏替代手术，如肝叶辅助移植或肝细胞移植，预计对这种疾病无效。在本文中，我们描述了一种新的技术，基于预备性肝脏照射和刺激肝细胞有丝分裂，通过失去肝脏质量或给予肝生长因子，允许移植的野生型肝细胞大量重新填充肝脏，取代受体小鼠肝脏中高达90%的肝细胞。将该方法应用于最近开发的agxt基因缺失的PH1小鼠模型，可显著改善高血氧症。我们建议进一步完善这一程序的不同组成部分，可能允许PHs的早期细胞治疗，从而预防肾功能衰竭及其并发症。版权所有(C) 2005 S. Karger AG，巴塞尔。
Primary hyperoxalurias (PHs) are diseases caused by overproduction of oxalate by hepatocytes. Most patients with PHs develop nephrocalcinosis and renal failure. Combined liver-kidney transplantation is often used as a definitive treatment of PHs, but because of a large body oxalate load at the time of transplantation, the procedure is not always successful. Because all hepatocytes overproduce oxalate, partial liver replacement procedures, such as auxiliary transplantation of a liver lobe or hepatocyte transplantation are not expected to be useful in this disorder. In this paper we describe novel techniques, based on preparative hepatic irradiation and stimulation of hepatocyte mitosis, through loss of liver mass or administration of hepatic growth factor, which permit transplanted wild-type hepatocytes to massively repopulate the liver, replacing up to 90% of the hepatocytes in recipient mouse livers. Application of this procedure in a recently developed Agxt-gene-deleted mouse model of PH1 resulted in marked amelioration of hyperoxaluria. We propose that further refinement of the different components of this procedure may permit early cell-based therapies of PHs, thereby preventing renal failure and its complications. Copyright (C) 2005 S. Karger AG, Basel.