Therapeutic Liver Reconstitution With Murine Cells Isolated Long After Death

Therapeutic Liver Reconstitution With Murine Cells Isolated Long After Death
Laura Erker
Received 24 December 2009; accepted 27 May 2010. published online 04 June 2010.

Abstract
Due to the shortage of donor organs, many patients needing liver transplantation cannot receive one. For some liver diseases, hepatocyte transplantation could be a viable alternative, but donor cells currently are procured from the same sources as whole organs, and thus the supply is severely limited.

Methods
Here, we investigated the possibility of isolating viable hepatocytes for liver cell therapy from the plentiful source of morgue cadavers. To determine the utility of this approach, cells were isolated from the livers of non–heart-beating cadaveric mice long after death and transplanted into fumarylacetoacetate hydrolase–deficient mice, a model for the human metabolic liver disease hereditary tyrosinemia type I and a stringent in vivo model for hepatic cell transplantation.

Results
Surprisingly, complete and therapeutic liver repopulation could be achieved with hepatocytes derived up to 27 hours post mortem.

Conclusions
Competitive repopulation experiments showed that cadaveric liver cells had a repopulation capacity similar to freshly isolated hepatocytes. Importantly, viable hepatocytes also could be isolated from cadaveric primate liver (monkey and human) efficiently. These data provide evidence that non–heart-beating donors could be a suitable source of hepatocytes for much longer time periods than previously thought possible.

Keywords: Fumarylacetoacetate Hydrolase (Fah)-Deficient Mice, Hereditary Tyrosinemia Type I, Liver Disease, Hepatocytes

Abbreviations used in this paper: AAV, adeno-associated virus, Fah, fumarylacetoacetate hydrolase, G6PD, glucose-6-phospho-diesterase, HNF4α, hepatocyte nuclear factor 4-α, NTBC, 2-(2-nitro-4-3 trifluoro-methylbenzoyl)-1,3-cyclohexanedione, PCR, polymerase chain reaction, R26R, Rosa26 reporter mice, Ttr, transthyretin receptor

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Therapeutic Liver Reconstitution With Murine Cells Isolated Long After Death

Affiliations
Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon
Reprint requests Address requests for reprints to: Laura Erker, PhD, Oregon Stem Cell Center, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, L-321, Portland, Oregon 97239. fax: (503) 418-5044
, Hisaya Azuma
Affiliations
Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon
, Andrew Y. Lee
Affiliations
Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California
Department of Surgery, Division of Transplantation, University of California, San Francisco, California
, Changsheng Guo
Affiliations
Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon
, Susan Orloff
Affiliations
Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon
, Laura Eaton
Affiliations
Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon
, Eric Benedetti
Affiliations
Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon
, Bryan Jensen
Affiliations
Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon
, Milton Finegold
Affiliations
Department of Pathology, Texas Children's Hospital, Houston, Texas
, Holger Willenbring
Affiliations
Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California
Department of Surgery, Division of Transplantation, University of California, San Francisco, California
, Markus Grompe
Affiliations
Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon
Papé Family Pediatric Research Institute, Portland, Oregon