Mesenchymal stem cell–derived molecules directly modulate... : Hepatology (original) (raw)
Liver Injury/Regeneration
Mesenchymal stem cell–derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo
van Poll, Daan1,2; Parekkadan, Biju1,3; Cho, Cheul H.1; Berthiaume, François1; Nahmias, Yaakov1; Tilles, Arno W.1; Yarmush, Martin L.1,3*
1_Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, MA_
2_Department of Surgery, University Medical Center, University of Utrecht, Utrecht, The Netherlands_
3_Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA_
*Address reprint requests to: 51 Blossom Street, Boston, MA 02114
Email:[email protected]
Received 17 September 2007; Accepted 14 January 2008
Published online in Wiley InterScience (www.interscience.wiley.com).
Grant sponsor: National Institutes of Health; Grant Numbers: K08 DK66040 K18 DK076819 R01 DK43371; Grant sponsor: Shriners Hospitals for Children; Grant sponsor: Fellowship from the National Science Foundation; Grant sponsor: Fellowship from the Michael van Vlooten Foundation.
Potential conflict of interest: Nothing to report.
These authors contributed equally to this study.
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Abstract
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. Conclusion: 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.
Abbreviations: ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; BrdU, bromodeoxyuridine; FHF, fulminant hepatic failure; HE, hematoxylin-eosin; IL, interleukin; MSC, mesenchymal stem cell; MSC-CM, mesenchymal stem cell–conditioned medium; PCNA, proliferating cell nuclear antigen; RT-PCR, reverse transcription polymerase chain reaction; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; TUNEL, terminal deoxynucleotidyl transferase-mediated nick-end labeling.
Copyright © 2008 American Association for the Study of Liver Diseases.