Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells.
OBJECTIVE
Liver transplantation is the primary treatment for various end-stage hepatic diseases but is hindered by the lack of donor organs and by complications associated with rejection and immunosuppression. There is increasing evidence to suggest the bone marrow is a transplantable source of hepatic progenitors. We previously reported that multipotent bone marrow-derived mesenchymal stem cells differentiate into functional hepatocyte-like cells with almost 100% induction frequency under defined conditions, suggesting the potential for clinical applications. The aim of this study was to critically analyze the various parameters governing the success of bone marrow-derived mesenchymal stem cell-based therapy for treatment of liver diseases.


METHODS
Lethal fulminant hepatic failure in nonobese diabetic severe combined immunodeficient mice was induced by carbon tetrachloride gavage. Mesenchymal stem cell-derived hepatocytes and mesenchymal stem cells were then intrasplenically or intravenously transplanted at different doses.


RESULTS
Both mesenchymal stem cell-derived hepatocytes and mesenchymal stem cells, transplanted by either intrasplenic or intravenous route, engrafted recipient liver, differentiated into functional hepatocytes, and rescued liver failure. Intravenous transplantation was more effective in rescuing liver failure than intrasplenic transplantation. Moreover, mesenchymal stem cells were more resistant to reactive oxygen species in vitro, reduced oxidative stress in recipient mice, and accelerated repopulation of hepatocytes after liver damage, suggesting a possible role for paracrine effects.


CONCLUSIONS
Bone marrow-derived mesenchymal stem cells can effectively rescue experimental liver failure and contribute to liver regeneration and offer a potentially alternative therapy to organ transplantation for treatment of liver diseases.
Kuo
Tom K
TK
Institute of Biopharmaceutical Science, National Yang-Ming University, Taipei, Taiwan.
Hung
Shun-Pei
SP
Chuang
Chiao-Hui
CH
Chen
Chien-Tsun
CT
Shih
Yu-Ru V
YR
Fang
Szu-Ching Y
SC
Yang
Vincent W
VW
Lee
Oscar K
OK
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002251:Carbon Tetrachloride; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*; D008115:Liver Regeneration; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
D000975:Antioxidants; D017382:Reactive Oxygen Species; D002251:Carbon Tetrachloride