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.
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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
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