American Surgical Association

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Topic: A. Basic Science
Generation of Humanized Animal Livers using Stem Cell Transplant
Jayme E Locke, Zhaoli Sun, Daniel S Warren, Timothy P Sheets, Horatio Holzer, Michael J Shamblott, Robert A. Montgomery, Andrew M Cameron
The Johns Hopkins University School of Medicine, Baltimore, MD

Objective: Animal organs engineered to be chimeric for human cells could contribute significantly to transplant surgery, allowing for study of human-specific diseases such as hepatitis-C, as treatment for in-born errors of metabolism, and for development of a source of transplantable organs via modified xenotransplantation. We sought to use human stem cells (HSC) to populate animal livers for applications in transplantation.
Methods: SCID mice and DA rats underwent liver injury with carbon tetrachloride or partial (50%) hepatectomy. Animals received intrasplenic injection of fluorescently labeled human stem cells. Spleen and liver were assessed at 2, 7, 15, and 30 days after transplant for the presence of HSCs and markers of human hepatocyte differentiation.
Results: HSCs migrate to and engraft in animal liver after splenic injection under conditions of hepatic injury. HSCs are detectable at 2-days and are in abundance at 1-week after transplant (1A,B). HSCs persist in rodent liver long-term (> 1 month), and once engrafted differentiate into functional human hepatocytes as assessed by production of human AFP and human albumin (1C).
Conclusions: We report a novel animal model in which hepatic injury and stem cell transplantation lead to the generation of humanized animal organs. We are currently utilizing our model to study recurrent hepatitis-C after liver transplantation and are now performing human stem cell transplants in miniature swine to generate a large animal preclinical model.


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