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.

Public Health Relevance

Liver diseases cause about 27,000 deaths annually in the US, 2,500 of which perish on the waiting list for liver transplant. A major reason of liver related deaths is the limited donor pool. This project aims to improve public health by utilizing currently discarded donor livers as natural scaffolds for stem cell-derived liver cells to constitute livers grafts to be transplantable with success.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Transition Award (R00)
Project #
5R00DK083556-06
Application #
8508932
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sherker, Averell H
Project Start
2011-09-20
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$224,793
Indirect Cost
$76,415
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Nishikawa, Taichiro; Bellance, Nad├Ęge; Damm, Aaron et al. (2014) A switch in the source of ATP production and a loss in capacity to perform glycolysis are hallmarks of hepatocyte failure in advance liver disease. J Hepatol 60:1203-11
Hansel, Marc C; Gramignoli, Roberto; Blake, William et al. (2014) Increased reprogramming of human fetal hepatocytes compared with adult hepatocytes in feeder-free conditions. Cell Transplant 23:27-38
Nagrath, Deepak; Soto-Gutierrez, Alejandro (2014) Reply to: "Is the pathway of energy metabolism modified in advanced cirrhosis?". J Hepatol 61:453
Dutta-Moscato, Joyeeta; Solovyev, Alexey; Mi, Qi et al. (2014) A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression. Front Bioeng Biotechnol 2:18
Duncan, Andrew W; Soto-Gutierrez, Alejandro (2013) Liver repopulation and regeneration: new approaches to old questions. Curr Opin Organ Transplant 18:197-202
Willenbring, Holger; Soto-Gutierrez, Alejandro (2013) Transplantable liver organoids made from only three ingredients. Cell Stem Cell 13:139-40
Yagi, Hiroshi; Soto-Gutierrez, Alejandro; Kitagawa, Yuko (2013) Whole-organ re-engineering: a regenerative medicine approach to digestive organ replacement. Surg Today 43:587-94