Engineering of hepatic grafts with decellularized native matrices

这是Soto-Gutierrez博士的职业资助申请；他是医学博士；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 他的兴趣已经转移到将这些工具应用于器官工程上。建立 作为器官工程领域的独立研究员，Soto-Gutierrez博士在本五年 由海伦·安德鲁斯·本尼迪克特赞助的马丁·雅穆什博士的职业发展计划 哈佛医学院外科和生物工程教授，美国疾病控制与预防中心主任 马萨诸塞州总医院的医学工程学，包括i)强化的动手培训 在器官工程中，隔离肝基质灌流和干细胞分化，ii)学术课程和 研讨会，以及(三)特别咨询委员会的指导。 我们的长期目标是开发一个天然的肝脏平台，使干细胞完全和稳定地成熟 肝细胞和设计功能性肝移植。拟议研究的目标是开发 体外灌流肝脏-基质-支架系统促进干细胞再生和肝脏成熟 肝源性细胞，并研究其在建立供移植的辅助肝移植物方面的应用。 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支架可以广泛地重新填充，并可以提供一种 干细胞来源的肝细胞有足够的成熟环境，这种器官培养体系可以 用于设计用于移植的代谢性功能性肝移植。这项研究的基本原理是 缺血损伤的、不可移植的器官的数量远远超过了目前的 它们为干细胞治疗提供了一个理想的平台。所描述的工作 预计将在以下方面：1)建立肝细胞再细胞化和植入方案 脱细胞基质，ii)为干细胞来源的肝细胞产生再繁殖和成熟系统， 以及iii)开发一种新的肝移植工程方法作为辅助肝支持移植 肝脏疾病。这项工作的结果也将产生积极影响，因为它建立了 未来复杂的器官工程技术的平台，融合了几种不同的细胞类型， 可应用于其他器官，并可能导致整个器官的体外发育。

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.