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Engineering of hepatic grafts with decellularized native matrices

使用脱细胞天然基质进行肝移植工程

基本信息

批准号：
8508932
负责人：
Alejandro Soto-Gutierrez
金额：
$ 22.48万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-20 至 2014-06-30
项目状态：
已结题

项目摘要

This is a career grant application for Dr. Soto-Gutierrez; an M.D.; Ph.D. who specializes in cell therapies and liver diseases. Dr. Soto-Gutierrez has recently developed novel methods of differentiating stem cells into liver cells, and his interests have shifted to application of such tools to organ engineering. To establish himself as an independent researcher in the field of organ engineering, Dr. Soto-Gutierrez submits this fiveyear career development plan under the sponsorship of Dr. Martin Yarmush, the Helen Andrus Benedict Professor of Surgery and Bioengineering at Harvard Medical School and the director of the Center for Engineering in Medicine at the Massachusetts General Hospital, which includes i) intensive hand-on training in organ engineering, isolated liver-matrices perfusion and stem cell differentiation, ii)academic courses and seminars, and iii) guidance of a select advisory committee. Our long-term goals are to develop a natural hepatic platform for complete and stable maturation of stemderived liver cells and to engineer functional liver grafts. The objectives of the proposed study are to develop an extracorporeal perfusion liver-matrix-scaffold system for repopulation and hepatic maturation of stem liver-derived cells, and investigate its employment for the creation of auxiliary liver grafts for transplantation in patients with impaired hepatic function. The central hypothesis to be tested here is that the decellularized natural liver scaffold, obtained from discarded livers, can be extensively repopulated and can provide an adequate maturation environment for stem derived liver cells, and this organ culture system can be employed to engineer metabolic functional liver grafts for transplantation. The rationale of the study is that ischemically damaged, untransplantable organs are available in numbers that far surpass the current demand, and they present an ideal platform for delivery for stem cell-based therapies. The work described here is expected to i) establish a protocol for recellularization and engraftment of hepatocyes in decellularized matrices, ii) generate a repopulation and maturation system for stem cell-derived hepatocytes, and iii) develop a novel method of liver graft engineering for transplantation as auxiliary liver support in hepatic diseases. The results of this work will also have a positive impact by establishing the basis and platform for future sophisticated organ engineering techniques that incorporates several different cell types, can be applied to other organs and may lead to development of entire organs in vitro.

这是 Soto-Gutierrez 博士的职业补助金申请；医学博士；博士专门从事细胞疗法和肝脏疾病。 Soto-Gutierrez 博士最近开发了将干细胞分化为肝细胞，他的兴趣已转向将此类工具应用于器官工程。建立索托-古铁雷斯博士本人作为器官工程领域的独立研究员，提交了这份五年报告 Martin Yarmush 博士、Helen Andrus Benedict 赞助的职业发展计划哈佛医学院外科与生物工程教授兼该中心主任马萨诸塞州总医院的医学工程，其中包括 i) 强化实践培训器官工程、离体肝脏基质灌注和干细胞分化，ii) 学术课程和研讨会，以及 iii) 特定咨询委员会的指导。我们的长期目标是开发一个天然的肝脏平台，使干细胞完全稳定地成熟。肝细胞并设计功能性肝移植物。拟议研究的目标是开发用于干细胞再增殖和肝成熟的体外灌注肝基质支架系统肝源性细胞，并研究其在创建用于移植的辅助肝移植物中的应用肝功能受损的患者。这里要测试的中心假设是脱细胞从废弃的肝脏中获得的天然肝脏支架可以广泛地重新填充，并可以提供为干细胞来源的肝细胞提供足够的成熟环境，并且该器官培养系统可以用于设计用于移植的代谢功能性肝移植物。该研究的基本原理是缺血性损伤、无法移植的器官数量远远超过目前需求，它们为基于干细胞的疗法提供了一个理想的平台。所描述的工作预计 i) 建立肝细胞再细胞化和植入的方案脱细胞基质，ii) 为干细胞衍生的肝细胞生成再增殖和成熟系统， iii) 开发一种新的肝移植工程方法，用于移植作为辅助肝脏支持肝脏疾病。这项工作的成果也将产生积极的影响，为建立基础和未来复杂的器官工程技术平台，融合了几种不同的细胞类型，可以应用于其他器官，并可能导致整个器官在体外发育。