Organogenesis of Ectopic Tissue in Lymph Node

描述(申请人提供)：我们的建议解决了开发复杂的三维组织模型的一些解决方案，并提出了一种新的范例，将淋巴结作为体内生物反应器来生长组织或器官替代品。我们最初的研究和概念验证将围绕终末期肝病患者的淋巴结异位肝的产生展开。肝细胞移植已被报道为肝病的一种可能的治疗方法。然而，移植针对的是肝脏本身，限制了终末期肝病患者的疗效，因为此时肝硬变和纤维化很常见。在这项建议中，我们证明了在淋巴结内产生异位肝脏是恢复肝功能的有效方法，突出了该器官作为肝细胞移植部位的新用途。供体肝细胞在淋巴结内的动态平衡扩张挽救了致死性肝衰竭。这些数据提供了第一个确凿的证据，证明功能异位肝脏可以挽救致命的肝病。此外，这种方法的有效性表明，淋巴结具有基于细胞的移植和组织工程的治疗潜力。我们在淋巴结中产生功能性肝组织的新范例将进一步应用于其他组织。 公共卫生相关性：我们的建议解决了开发复杂的3-D组织模型所面临的一些障碍，并提供了一种新的组织建模范式，将淋巴结用作体内生物反应器来种植组织或器官替代品。

DESCRIPTION (provided by applicant): Our proposal addresses some of the solutions to the development of complex 3- dimensional tissue models and a new paradigm by using lymph node as in vivo bioreactors to grow tissue or organ substitute. Our initial study and prove of concept will be centered around the generation of ectopic liver in lymph nodes for patients suffering end-stage liver diseases. Hepatocyte transplantation has been reported as a possible therapeutic approach for liver disease. However, transplantation has been directed at the liver itself, limiting efficacy in patients with end-stage liver diseases, when cirrhosis and fibrosis are common. In this proposal we demonstrate that the generation of an ectopic liver within lymph nodes is an efficient method to restore hepatic function, highlighting the novel use of this organ as a site for hepatocyte transplantation. Homeostatic expansion of donor hepatocytes in lymph nodes resulted in the rescue of lethal hepatic failure. These data provide the first definitive evidence that a functional ectopic liver can rescue lethal hepatic diseases. Furthermore, with the efficacy of this approach suggests that lymph nodes have therapeutic potential for cell-based transplantation and tissue engineering. Our new paradigm to generate functional liver tissues in lymph nodes will be further applied to other tissues. PUBLIC HEALTH RELEVANCE: Our proposal addresses some of the hurdles confronting the development of complex 3-D tissue models, and provides a new paradigm for tissue modeling, by using lymph nodes as in vivo bioreactors to grow tissue or organ substitutes.