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Restoration of Liver Function Following Transplantation of Healthy Hepatocytes into the Fah ‐/‐ IL2rg ‐/‐ Rat Model
Author(s) -
Rasmussen Shauna,
Mallanna Sunil,
LerchGaggl Alexandra,
North Paula,
Fahrenkrug Scott,
Carlson Daniel,
Tan Wenfang,
Wilson Elizabeth,
Duncan Stephen,
Geurts Aron
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb681
Subject(s) - hepatocyte , transplantation , transgene , xenotransplantation , chemistry , albumin , andrology , microbiology and biotechnology , medicine , biology , endocrinology , biochemistry , in vitro , gene
Immune‐compromised mouse models of Hereditary Tyrosinemia Type I, which are deficient in fumarylacetoacetate hydrolase ( Fah ), have been widely appreciated as robust models for hepatocyte xenotransplantation studies. We hypothesized that a similar rat model with its increased size and ease of surgical procedures might provide unique experimental advantages. With the use of transcriptional activator‐like effector nuclease (TALEN) technology, we generated a Fah ‐/‐ ;Interleukin 2 receptor gamma ( IL2rg ) ‐/‐ double knockout rat and examined whether this model could undergo transplantation of healthy hepatocytes from either rat or human sources to restore liver function over time. Hepatocytes isolated from a green fluorescent protein (GFP) transgenic rat or commercially available human hepatocytes were injected intrasplenically into Fah ‐/‐ IL2rg ‐/‐ rats. Animals were cycled off/on 2‐[2‐nitro‐4‐(trifluoromethyl)benzoyl] cyclohexane‐1,3‐dione (NTBC) in order to obtain engraftment of the transplanted cells. Correction of liver function and robust engraftment of GFP (+) hepatocytes (2.12‐76.46%; n=25) were seen in the liver after one or three months of NTBC cycling. Human albumin was detected in serum (1µg/ml‐60µg/ml; n=5) of rats transplanted with human hepatocytes. This data supports that our Fah ‐/‐ IL2rg ‐/‐ rat model demonstrates effective engraftment and clonal expansion of transplanted healthy hepatocytes.