This is a career grant application for Dr. Soto-Gutierrez;an M.D.;[sic] 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 five-year 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 stem-derived 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 is chemically 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 hepatocytes [sic] 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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Career Transition Award (K99)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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University of Pittsburgh
Schools of Medicine
United States
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Handa, Kan; Matsubara, Kentaro; Fukumitsu, Ken et al. (2014) Assembly of human organs from stem cells to study liver disease. Am J Pathol 184:348-57
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
Yagi, Hiroshi; Fukumitsu, Ken; Fukuda, Kazumasa et al. (2013) Human-scale whole-organ bioengineering for liver transplantation: a regenerative medicine approach. Cell Transplant 22:231-42
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
Wertheim, Jason A; Baptista, Pedro M; Soto-Gutierrez, Alejandro (2012) Cellular therapy and bioartificial approaches to liver replacement. Curr Opin Organ Transplant 17:235-40
Soto-Gutierrez, Alejandro; Wertheim, Jason A; Ott, Harald C et al. (2012) Perspectives on whole-organ assembly: moving toward transplantation on demand. J Clin Invest 122:3817-23
Fukumitsu, K; Yagi, H; Soto-Gutierrez, A (2011) Bioengineering in organ transplantation: targeting the liver. Transplant Proc 43:2137-8
Soto-Gutierrez, Alejandro; Zhang, Li; Medberry, Chris et al. (2011) A whole-organ regenerative medicine approach for liver replacement. Tissue Eng Part C Methods 17:677-86
Uygun, K; Tolboom, H; Izamis, M L et al. (2010) Diluted blood reperfusion as a model for transplantation of ischemic rat livers: alanine aminotransferase is a direct indicator of viability. Transplant Proc 42:2463-7
van Poll, Daan; Nahmias, Yakoov; Soto-Gutierrez, Alejandro et al. (2010) Human immune reactivity against liver sinusoidal endothelial cells from GalT?(1,3)GalT-deficient pigs. Cell Transplant 19:783-9

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