Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo.
Orthotopic liver transplantation is the only proven effective treatment for fulminant hepatic failure (FHF), but its use is limited because of organ donor shortage, associated high costs, and the requirement for lifelong immunosuppression. FHF is usually accompanied by massive hepatocellular death with compensatory liver regeneration that fails to meet the cellular losses. Therefore, therapy aimed at inhibiting cell death and stimulating endogenous repair pathways could offer major benefits in the treatment of FHF. Recent studies have demonstrated that mesenchymal stem cell (MSC) therapy can prevent parenchymal cell loss and promote tissue repair in models of myocardial infarction, acute kidney failure, and stroke through the action of trophic secreted molecules. In this study, we investigated whether MSC therapy can protect the acutely injured liver and stimulate regeneration. In a D-galactosamine-induced rat model of acute liver injury, we show that systemic infusion of MSC-conditioned medium (MSC-CM) provides a significant survival benefit and prevents the release of liver injury biomarkers. Furthermore, MSC-CM therapy resulted in a 90% reduction of apoptotic hepatocellular death and a three-fold increment in the number of proliferating hepatocytes. This was accompanied by a dramatic increase in the expression levels of 10 genes known to be up-regulated during hepatocyte replication. Direct antiapoptotic and promitotic effects of MSC-CM on hepatocytes were demonstrated using in vitro assays.


CONCLUSIONS
These data provide the first clear evidence that MSC-CM therapy provides trophic support to the injured liver by inhibiting hepatocellular death and stimulating regeneration, potentially creating new avenues for the treatment of FHF.
van Poll
Daan
D
Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, MA, USA.
Parekkadan
Biju
B
Cho
Cheul H
CH
Berthiaume
François
F
Nahmias
Yaakov
Y
Tilles
Arno W
AW
Yarmush
Martin L
ML
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000503:physiopathology* / Q000601:surgery*; D016923:Cell Death; D006801:Humans; D017093:Liver Failure / Q000601:surgery*; D008111:Liver Function Tests; D008113:Liver Neoplasms / Q000473:pathology* / Q000503:physiopathology* / Q000601:surgery*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D014183:Transplantation, Heterologous
D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase