Bone marrow-derived liver stem cell and mature hepatocyte engraftment in livers undergoing rejection.
BACKGROUND
The definitive therapy for end-stage liver disease is orthotopic liver transplantation (OLT). However, rejection is still a major cause of mortality and morbidity following OLT. Hepatocyte transplantation has been used experimentally to treat liver diseases. The aim of this study was to investigate whether bone marrow-derived liver stem cells (BDLSC) and mature hepatocytes could repopulate transplanted livers undergoing rejection.


METHODS
OLT was carried out from D'Agouti (C3-positive female) into Lewis (C3-negative female) rats. BDLSC were transplanted from Lewis (male) into livers of D'Agouti (female) rats. Group A (n = 9) received intraportal normal saline. Groups B (n = 9) and C (n = 9) underwent intraportal transplantation of mature hepatocytes (Lewis female, 0.75 x 10(7)) and DBLSC (Lewis male, 5 x 10(4)) respectively. All groups received subtherapeutic immunosuppression (Cyclosporin 0.25 mg/kg/d) for 13 days. Liver repopulation was assessed using immunohistochemistry (C3 antigen-negative cells), in-situ hybridization, (Y-chromosome-positive BDLSC) and histologic assessment (hematoxylin and eosin) for rejection.


RESULTS
BDLSC and mature hepatocytes repopulated 62 +/- 12.3% and 2.5 +/- 1.7% of rejecting livers, respectively. BDLSC demonstrated formation of hepatic lobules and portal triads with little evidence of rejection 36 days after discontinuation of immunosuppression.


CONCLUSIONS
BDLSC can repopulate livers undergoing severe rejection. Moreover, BDLSC can differentiate into hepatocytes and cholangiocytes. This finding may have important clinical implications.
Avital
Itzhak
I
Department Of Surgery, Liver Support Research Laboratory, Cedars-Sinai Medical Center, UCLA School Of Medicine, 90048, USA.
Feraresso
Chiara
C
Aoki
Takeshi
T
Hui
Thomas
T
Rozga
Jacek
J
Demetriou
Achilles
A
Muraca
Maurizio
M
D000818:Animals; D005260:Female; D006084:Graft Rejection / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D022781:Hepatocytes / Q000166:cytology / Q000637:transplantation*; D017093:Liver Failure / Q000601:surgery; D008115:Liver Regeneration; D016031:Liver Transplantation; D009336:Necrosis; D051381:Rats; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous