Engineering of hepatic grafts with decellularized native matrices

这是索托-古铁雷斯博士的职业资助申请，他是医学博士博士专门研究细胞疗法， 肝脏疾病索托-古铁雷斯博士最近开发了一种新的方法， 他的兴趣已经转移到将这些工具应用于器官工程。建立 作为器官工程领域的独立研究人员，索托-古铁雷斯博士提交了这份为期五年的报告。 在马丁·雅穆什博士的赞助下，海伦·安德鲁斯·本尼迪克特的职业发展计划 哈佛医学院外科和生物工程学教授， 在马萨诸塞州总医院的医学工程，其中包括i）密集的动手培训 在器官工程，离体肝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，使干细胞源性 肝细胞和设计功能性肝移植物。拟议研究的目的是发展 一种体外灌注肝基质支架系统用于干细胞的再增殖和肝成熟 肝源性细胞，并探讨其就业的创造辅助肝移植移植 在肝功能受损的患者中。这里要检验的中心假设是，脱细胞的 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，并且可以提供一种新的治疗方法。 为干细胞衍生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。这项研究的基本原理是， 缺血性损伤，不可移植的器官数量远远超过目前 他们提供了一个理想的平台，用于基于干细胞的治疗。描述的工作 本文预期i）建立肝细胞再细胞化和植入的方案， 脱细胞基质，ii）产生干细胞衍生的肝细胞的再增殖和成熟系统， 和iii）开发用于移植的肝移植物工程的新方法作为辅助肝支持， 肝脏疾病这项工作的结果也将产生积极的影响， 未来复杂器官工程技术的平台，包括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。

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.