Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo
- H Aurich1,
- M Sgodda1,
- P Kaltwaßer2,
- M Vetter3,
- A Weise4,
- T Liehr4,
- M Brulport5,
- J G Hengstler5,
- M M Dollinger1,
- W E Fleig1,6,
- B Christ1
- 1First Department of Medicine, Martin Luther University of Halle–Wittenberg, Germany
- 2Center of Reproductive Medicine and Andrology, Martin Luther University of Halle–Wittenberg, Germany
- 3Clinic for Gynecology, Martin Luther University of Halle–Wittenberg, Germany
- 4Institut für Humangenetik und Anthropologie, University of Jena School of Medicine, Germany
- 5Leibniz Research Centre for Working Environment and Human Factors, University of Dortmund, Germany
- 6University of Leipzig Hospitals and Clinics, Germany
- Professor Dr B Christ, First Department of Medicine, Martin Luther University of Halle–Wittenberg, Heinrich-Damerow-Straße 1, D-06120 Halle/Saale, Germany;
- Revised 24 September 2008
- Accepted 30 October 2008
- Published Online First 20 November 2008
Objective: The hepatic integration of human adipose tissue derived mesenchymal stem cells (hAT-MSCs) in vivo with or without prior differentiation to hepatocyte-like cells in vitro was investigated.
Methods and results: Cells, isolated either from peritoneal or subcutaneous adipose tissue, expressed mesenchymal stem cell surface markers and featured multiple lineage differentiation. Under conditions favouring hepatocyte differentiation, hAT-MSCs gained hepatocytic functions in vitro including urea formation, glycogen synthesis, cytochrome P450 enzyme activity, and expression of hepatocyte-specific transcripts of carbamoylphosphate synthetase, albumin and cytochrome P450 type 3A4 (CYP3A4). Transgenic expression of green fluorescent protein emerged upon hepatocyte differentiation when driven by the hepatocyte-specific promoter of the cytosolic phosphoenolpyruvate carboxykinase gene but was constitutive from the ubiquitin gene promoter. Human AT-MSCs were transplanted into livers of immunodeficient Pfp/Rag2−/− mice with or without prior hepatocyte differentiation in vitro. Donor-derived human cells engrafted in the mouse host liver predominantly in the periportal region of the liver lobule. They expressed HepPar1 and albumin, typical features of differentiated human hepatocytes, in the otherwise negative mouse liver background. Engraftment was significantly more efficient using hAT-MSCs pre-differentiated to hepatocyte-like cells in vitro as compared with undifferentiated cells.
Conclusions: Pre-differentiation of human MSCs from adipose tissue into hepatocyte-like cells in vitro facilitates long term functional hepatic integration in vivo.
Competing interests: None.
Funding: This study was supported by The German Ministry of Education and Research (to BC: NBL3-NG4 and MD: BMBF, PtJ-Bio, 0313909, 1106SF), The Federal State of Saxonia–Anhalt and the German Ministry of Education and Research through the Wilhelm-Roux-Program at the Medical Faculty of the Martin Luther University of Halle–Wittenberg (to BC: 09/07, 04/03, 14/38, 16/06; and to HA: 13/03, 2/03).
Ethics approval: Approval for the use of human cells and tissue in this study was given by the Institutional Ethics Review Board on 1 March 2006 and 18 January 2008. All experimental procedures in mice were in accordance with German legislation on animal protection.
See Commentary, p 480
▸ A supplementary figure is published online only at http://gut.bmj.com/content/vol58/issue4