Allogeneic bone marrow transplantation restores liver function in Fah-knockout mice.
OBJECTIVE
In murine models, transplantation of wild-type bone marrow cells (BMC) can counterbalance genetic liver defects by fusion between transplanted marrow cells and resident hepatocytes. This phenomenon, however, is of no immediate clinical use because all syngeneic BMC harbor the same underlying genetic defect.


METHODS
Describing the fusion between transplanted allogeneic BMC and resident hepatocytes in a murine model of hereditary tyrosinemia type I (fumarylacetoacetate hydrolase [Fah] knockout mouse), we transplanted BMC from fully allogeneic BALB/c donors into Fah(-/-) recipients after lethal total body irradiation.


RESULTS
Following hematopoietic reconstitution, recipients remained healthy without pharmacological support (withdrawal of 2-2-nitro-4-fluoromethylbenzoyl-1,3-cyclohexanedione [NTBC]). Metabolic serum parameters improved nearly to wild-type levels. Livers of recipient animals contained up to 10% functional hepatocytes that stained positive for wild-type Fah, as well as both donor and recipient major histocompatibility complex. Flow cytometry confirmed this coexpression on a single cell level. Application of T-cell-depleted bone marrow reduced onset of early graft-vs-host disease.


CONCLUSIONS
We introduce the observation that allogeneic bone marrow transplantation can lead to stable cell fusion of BMC with recipient hepatocytes and restored liver function in a model of otherwise lethal genetic liver disease. Thus, in principle, allogeneic cell fusion can be a possible management of hereditary liver diseases. Long-term immunological properties of fusion cells have to be further investigated.
Eggenhofer
Elke
E
Department of Surgery, University of Regensburg, Regensburg, Germany.
Popp
Felix C
FC
Renner
Philipp
P
Slowik
Pczemyslaw
P
Neuwinger
Annette
A
Piso
Pompiliu
P
Geissler
Edward K
EK
Schlitt
Hans J
HJ
Dahlke
Marc H
MH
D000818:Animals; D016026:Bone Marrow Transplantation; D022781:Hepatocytes / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D006867:Hydrolases / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D014184:Transplantation, Homologous
D015395:Histocompatibility Antigens Class I; D006867:Hydrolases; C020156:fumarylacetoacetase