The bone marrow functionally contributes to liver fibrosis.
OBJECTIVE
Bone marrow (BM) cells may transdifferentiate into or fuse with organ parenchymal cells. BM therapy shows promise in murine models of cirrhosis, and clinical trials of bone marrow stem cell therapy for organ healing are underway. However, the BM may contribute to scar-forming myofibroblasts in various organs including the liver. We have studied this axis of regeneration and scarring in murine models of cirrhosis, including an assessment of the temporal and functional contribution of the BM-derived myofibroblasts.


METHODS
Female mice were lethally irradiated and received male BM transplants. Carbon tetrachloride or thioacetamide was used to induce cirrhosis. BM-derived cells were tracked through in situ hybridization for the Y chromosome. BM transplants from 2 strains of transgenic mice were used to detect intrahepatic collagen production.


RESULTS
In the cirrhotic liver, the contribution of BM to parenchymal regeneration was minor (0.6%); by contrast, the BM contributed significantly to hepatic stellate cell (68%) and myofibroblast (70%) populations. These BM-derived cells were found to be active for collagen type 1 transcription in 2 independent assays and could influence the fibrotic response to organ injury. These BM-derived myofibroblasts did not occur through cell fusion between BM-derived cells and indigenous hepatic cells but, instead, originated largely from the BM's mesenchymal stem cells.


CONCLUSIONS
The BM contributes functionally and significantly to liver fibrosis and is a potential therapeutic target in liver fibrosis. Clinical trials of BM cell therapy for liver regeneration should be vigilant for the possibility of enhanced organ fibrosis.
Russo
Francesco P
FP
Department of Medicine, Imperial College, London, United Kingdom.
Alison
Malcolm R
MR
Bigger
Brian W
BW
Amofah
Eunice
E
Florou
Aikaterini
A
Amin
Farhana
F
Bou-Gharios
George
G
Jeffery
Rosemary
R
Iredale
John P
JP
Forbes
Stuart J
SJ
D000818:Animals; D001707:Biopsy, Needle; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000379:methods; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000473:pathology* / Q000628:therapy*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010784:Photomicrography; D012680:Sensitivity and Specificity; D013997:Time Factors