Organogenesis of Ectopic Tissue in Lymph Node

描述（由申请人提供）：我们的提案提出了开发复杂三维组织模型的一些解决方案，以及通过使用淋巴结作为体内生物反应器来生长组织或器官替代物的新范例。我们的初步研究和概念证明将集中在患有终末期肝病的患者的淋巴结中异位肝脏的产生。肝细胞移植已被报道为肝脏疾病的一种可能的治疗方法。然而，移植一直针对肝脏本身，限制了终末期肝病患者的疗效，此时肝硬化和纤维化很常见。在这个提议中，我们证明了在淋巴结内异位肝脏的产生是恢复肝功能的有效方法，突出了该器官作为肝细胞移植位点的新用途。淋巴结中供体肝细胞的稳态扩张导致了致命肝衰竭的挽救。这些数据提供了第一个明确的证据，功能性异位肝脏可以挽救致命的肝脏疾病。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：我们的建议解决了复杂的3-D组织模型的发展所面临的一些障碍，并提供了一个新的组织建模的范例，通过使用淋巴结作为体内生物反应器来生长组织或器官替代品。

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.