Liver Reengineering

Massachusetts General Hospital, Boston MA

Investigators

Abstract

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5) 0853569 Uygun There is a critical shortage of organs, with the organ waiting list currently at 100,000 requests and increasing by 5% every year. This study focuses on the liver: 27,000 die in the US annually due to liver disease, 4,000 essentially because they cannot get a transplant. A long-term solution to donor organ availability is to utilize embryonic stem cells to generate new hepatocytes for cell transplantation. However, the delivery of cells directly is inefficient due to low engraftment, and a tissue-engineered vehicle to ensure cell engraftment, viability, and functionality in the long term is a necessity to make cell transplantation work clinically. Such a scaffold has so far proven difficult to manufacture in vitro. The long-term goal of this research is to develop a natural hepatic scaffold for complete and stable maturation of stem-derived liver cells, ultimately for treatment of organ insufficiency or failure. The objective of this project is to develop a decellularized organ bioscaffold for embryonic stem-cell derived hepatocyte 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 of delivery for stem cell-based therapies. As a result this study is expected to i) create a new platform for cell transplantation, and ii) identify the role of native liver extracellular matrix in hepatic differentiation of embryonic stem cells. Intellectual merits. Scientifically, the identification of the role of native extracellular matrix in stem cell differentiation may lead to much more effective and efficient stem cell differentiation protocols, thus addressing the other bottleneck in tissue engineering which is a practical source for adult human cells. The recellularized bioscaffold could also be employed as a whole-organ model for drug development and testing and pharmaceutical studies. Finally, this work is expected to lead to sophisticated whole-organ tissue engineering approaches with potential of developing entire organs in vitro. Clinically, the recellularized liver bioscaffold could provide much needed alternatives to liver transplantation. Further, it could be used as a partial liver support to prevent liver insufficiency, in cases such as extensive hepatic resections in cancer patients and left lateral graft transplantation - a donor-safe alternative which is currently used for children but is not sufficient to treat adult patients. Finally, the grafts could be potentially used to treat inborn liver diseases, as vessel for healthy hepatocyte transplantation, leading to repopulation of the patient liver. Broader Impacts. The goal in Education is to train graduate students and undergraduate students in tissue engineering, stem cell engineering, surgical techniques, and quantitative systems biology. Further, based on this research, teaching modules for undergraduate education in chemical engineering/bioengineering will be developed and integrated to coursework by the research team and collaborators, as projects in undergraduate and graduate courses. These modules include a classroom decellularization display system, and an interactive software module to be freely distributed. These teaching modules and the study results will also be submitted for publication in educational and scientific journals to enhance dissemination. The development of a graft engineering methodology is expected to become a major enabling technology in tissue engineering and ultimately make an impact on society by providing a practical treatment for thousands of patients with liver failure.