Bone marrow-derived cells promote liver regeneration in mice with erythropoietic protoporphyria.
BACKGROUND
Bone marrow transplantation can reverse hepatic protoporphyrin accumulation and prevent the hepatobiliary complications characteristic of erythropoietic protoporphyria. The aim of this study was to assess the recruitment capacity of bone marrow cells in the damaged liver and their possible contribution to the improved or recovered hepatic function in a murine model of erythropoietic protoporphyria (EPP).


METHODS
Lethally irradiated female EPP mice were transplanted with bone marrow cells from healthy male mice and were monitored during 12 or 36 weeks. Two groups of animals killed 12 weeks after transplant were also treated with granulocyte colony-stimulating factor.


RESULTS
Cell transplantation decreased porphyrin contents in erythrocytes and liver. Improved hepatic structure and function and reduced hepatic fibrosis were observed, especially 36 weeks after transplant. Bone marrow-derived cells (22%-35%) were identified in the liver of recipient mice by means of fluorescence in situ hybridization (chrY-FISH) or green fluorescent protein staining and were characterized by immunofluorescence staining. The livers of recipients contained 20% to 30% myofibroblasts (alpha-smooth muscle actin-positive cells), 40% CK19-positive cells, and 10% to 28% hepatocytes (albumin-positive cells) derived from the donor bone marrow.


CONCLUSIONS
Bone marrow-derived cells play a significant role in restoring and regenerating hepatic tissue in EPP mice. Hepatic repair was associated with fibrogenesis, enhanced by granulocyte colony-stimulating factor treatment, and almost normal liver structure and function was observed in the long term (36 weeks posttransplant).
García-Bravo
María
M
Research Centre 12 de Octubre University Hospital, Madrid, Spain. maria.garciabravo@ciemat.es
Morán-Jiménez
María-Josefa
MJ
Quintana-Bustamante
Oscar
O
Méndez
Manuel
M
Gutiérrez-Vera
Inmaculada
I
Bueren
Juan
J
Salido
Eduardo
E
Segovia
José-Carlos
JC
Fontanellas
Antonio
A
de Salamanca
Rafael Enríquez
RE
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D016026:Bone Marrow Transplantation / Q000379:methods*; D004195:Disease Models, Animal; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D017404:In Situ Hybridization, Fluorescence; D008099:Liver / Q000473:pathology*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D046351:Protoporphyria, Erythropoietic / Q000188:drug therapy / Q000473:pathology / Q000601:surgery*; D011994:Recombinant Proteins; D016896:Treatment Outcome
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor