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Presenter: Roberto, Gramignoli, Pittsburgh, United States
Authors: Roberto Gramignoli1, Kenneth Dorko1, Veysel Tahan1, Kristen Skvorak1, March C. Hansel1, Raman Venkataramanan2, George Mazariegos3, Kyle Soltys3, Ira J. Fox3, Ewa C.S. Ellis4, Stephen C. Strom1
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Hepatocytes from metabolic disease patients: a potential cell source for domino transplant
Roberto Gramignoli1, Kenneth Dorko1, Veysel Tahan1, Kristen Skvorak1, March C. Hansel1, Raman Venkataramanan2, George Mazariegos3, Kyle Soltys3, Ira J. Fox3, Ewa C.S. Ellis4, Stephen C. Strom1
1Pathology, University of Pittsburgh; 2Pharmaceutical Sciences, University of Pittsburgh; 3Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States; 4Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden
Most inborn errors of metabolism are caused by single defects in an enzyme or transport protein that alters a metabolic pathway. Although individually rare, considered together, liver-based metabolic diseases represent approximately 10% of pediatric liver transplants and, in many centers, are the second most common indication for liver transplant after biliary atresia. Hepatocyte transplantation has been proposed as an alternative to liver transplantation for certain metabolic liver diseases. A major obstacle is the limited supply of donor tissue for cell isolation. Many tissues available for hepatocyte isolation are from organ donors (OD) rejected for organ transplant and are of marginal quality. We analyzed hepatocytes from 11 different metabolic diseases in term of recovery, viability, plating efficiency, ammonia and drug metabolizing capacity. Long-term hepatocyte quality was accessed by the expression and metabolic activity of Cytochrome P450 (CYP) 3A4, 3A7, 2C9 and 1A1/2 both on freshly isolated cells and in vitro after exposure to prototypical inducing agents. We obtained cells with acceptable viability and function from most of the 26 metabolic cases analyzed (viability 79±20% compared to 77±13% from 33 OD) and the mean plating efficiency of these cells was higher than those from ODs. Organs with urea cycle defects provided cells with an expectedly low (or null) capacity to metabolize ammonia, however they showed robust CYP activity immediately after isolation and surprisingly high activity after induction (up to 5 times the best OD). Cells isolated from diseases such as Oxalosis, Crigler-Najjar or Maple Syrup Urine Disease provided cells with robust phase I and II activities. Cirrhotic or cholestatic tissues such as Biliary Atresia provided cells which varied in quality with each donor. These results suggest it is reasonable to investigate hepatocyte domino transplant with cells obtained from donors with metabolic diseases with specifically matched recipients.
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