Mesenchymal Stem Cell-Derived Molecules Reverse Fulminant Hepatic Failure
| Title: | Mesenchymal Stem Cell-Derived Molecules Reverse Fulminant Hepatic Failure |
| Author: |
van Poll, Daan; Suganuma, Kazuhiro; Parekkadan, Biju; Carter, Edward Albert; Tilles, Arno W.; Yarmush, Martin Leon
Note: Order does not necessarily reflect citation order of authors. |
| Citation: | Parekkadan, Biju, Daan van Poll, Kazuhiro Suganuma, Edward A. Carter, François Berthiaume, Arno W. Tilles, and Martin L. Yarmush. 2007. Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. PLoS ONE 2(9): e941. |
| Full Text & Related Files: |
1978513.pdf (358.3Kb; PDF) 
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| Abstract: | Modulation of the immune system may be a viable alternative in the treatment of fulminant hepatic failure (FHF) and can potentially eliminate the need for donor hepatocytes for cellular therapies. Multipotent bone marrow-derived mesenchymal stem cells (MSCs) have been shown to inhibit the function of various immune cells by undefined paracrine mediators in vitro. Yet, the therapeutic potential of MSC-derived molecules has not been tested in immunological conditions in vivo. Herein, we report that the administration of MSC-derived molecules in two clinically relevant forms-intravenous bolus of conditioned medium (MSC-CM) or extracorporeal perfusion with a bioreactor containing MSCs (MSC-EB)-can provide a significant survival benefit in rats undergoing FHF. We observed a cell mass-dependent reduction in mortality that was abolished at high cell numbers indicating a therapeutic window. Histopathological analysis of liver tissue after MSC-CM treatment showed dramatic reduction of panlobular leukocytic infiltrates, hepatocellular death and bile duct duplication. Furthermore, we demonstrate using computed tomography of adoptively transferred leukocytes that MSC-CM functionally diverts immune cells from the injured organ indicating that altered leukocyte migration by MSC-CM therapy may account for the absence of immune cells in liver tissue. Preliminary analysis of the MSC secretome using a protein array screen revealed a large fraction of chemotactic cytokines, or chemokines. When MSC-CM was fractionated based on heparin binding affinity, a known ligand for all chemokines, only the heparin-bound eluent reversed FHF indicating that the active components of MSC-CM reside in this fraction. These data provide the first experimental evidence of the medicinal use of MSC-derived molecules in the treatment of an inflammatory condition and support the role of chemokines and altered leukocyte migration as a novel therapeutic modality for FHF. |
| Published Version: | doi:10.1371/journal.pone.0000941 |
| Other Sources: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1978513/pdf/ |
| Terms of Use: | This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA |
| Citable link to this page: | http://nrs.harvard.edu/urn-3:HUL.InstRepos:4621714 |
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