Stem Cell Therapy for Liver Disease: Parameters Governing the Success of Using Bone Marrow Mesenchymal Stem Cells

doi:10.1053/j.gastro.2008.03.015

Gastroenterology

Volume 134, Issue 7, June 2008, Pages 2111-2121.e3

https://doi.org/10.1053/j.gastro.2008.03.015 Get rights and content

Background & Aims: 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.

Section snippets

Materials and Methods

Details of the materials and methods used are described in the supplementary material (see supplementary material online at www.gastrojournal.org). A brief summary of the animal model and cells used for transplantation is given in the following text.

MSCs and MDHs Rescue Lethal Fulminant Hepatic Failure

The lethality of CCl₄ on NOD-SCID mice was tested by gavage. We determined that doses at ≤0.24 mL/kg body wt could not induce sufficient lethality, while doses at ≥0.32 mL/kg body wt elicited hyperacute injuries leading to rapid death. A dose of 0.28 mL/kg body wt was deemed optimal, resulting in lethality in all animals at 6 days after administration of CCl₄ (Figure 1A). All subsequent experiments were therefore performed at this dose. Biochemical assays showed a dramatic elevation in the

Discussion

Using a murine model of lethal chemically induced FHF, we investigated various parameters governing the success and efficacy of using MSCs as an alternative cell source to hepatocyte transplantation for treatment of liver disease. Our data show that MDHs are a potential alternative transplantable cell source for the treatment of FHF. However, transplantation of MSCs improved the rescuing efficiency compared with MDHs. Further enhancements were accomplished by systemic transplantation compared

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: Supported by the National Science Council, Taiwan (grants NSC 95-2745-B-075-002-MY3 and NSC 95-2314-B-075-014-MY2), by the intramural grant from the Taipei Veterans General Hospital, Taiwan (grant V96S4-026), and by the Liver Disease Prevention and Treatment Research Foundation, Taiwan.

: The authors report that no conflicts of interest exist.

View full text

Basic–Liver, Pancreas, and Biliary TractStem Cell Therapy for Liver Disease: Parameters Governing the Success of Using Bone Marrow Mesenchymal Stem Cells

Section snippets

Materials and Methods

MSCs and MDHs Rescue Lethal Fulminant Hepatic Failure

Discussion

Gastroenterology

Gastroenterology

J Hepatol

Hepatology

Blood

Bone

Blood

Liver Transpl

Blood

Biochem Pharmacol

Life Sci

Exp Hematol

J Hepatol

Advances in hepatocyte transplantation: a myth becomes reality

J Clin Invest

Emerging therapies in hepatology: liver-directed gene transfer and hepatocyte transplantation

Cells Tissues Organs

Liver repopulation: a new concept of hepatocyte transplantation

Surg Today

Cryopreservation of hepatocytes: a review of current methods for banking

Cell Tissue Bank

Bone marrow as a potential source of hepatic oval cells

Science

Hepatocytes from non-hepatic adult stem cells

Nature

Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion

Nature

Cell fusion is the principal source of bone-marrow-derived hepatocytes

Nature

Transplanted bone marrow regenerates liver by cell fusion

Nature

Mesenchymal stem cells in autoimmune disease

Stem Cells Dev

Basic–Liver, Pancreas, and Biliary Tract
Stem Cell Therapy for Liver Disease: Parameters Governing the Success of Using Bone Marrow Mesenchymal Stem Cells