Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo.
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.


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.
Aurich
H
H
First Department of Medicine, Martin Luther University of Halle-Wittenberg, Heinrich-Damerow-Strasse 1, D-06120 Halle/Saale, Germany.
Sgodda
M
M
Kaltwasser
P
P
Vetter
M
M
Weise
A
A
Liehr
T
T
Brulport
M
M
Hengstler
J G
JG
Dollinger
M M
MM
Fleig
W E
WE
Christ
B
B
D000273:Adipose Tissue / Q000166:cytology*; D053687:Adult Stem Cells / Q000166:cytology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D006085:Graft Survival; D022781:Hepatocytes / Q000166:cytology* / Q000502:physiology / Q000637:transplantation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008115:Liver Regeneration / Q000502:physiology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008817:Mice, Mutant Strains; D014183:Transplantation, Heterologous
D015703:Antigens, CD