Fate of extrahepatic human stem and precursor cells after transplantation into mouse livers.
In recent years, a large number of groups studied the fate of human stem cells in livers of immunodeficient animals. However, the interpretation of the results is quite controversial. We transplanted 4 different types of human extrahepatic precursor cells (derived from cord blood, monocytes, bone marrow, and pancreas) into livers of nonobese diabetic/severe combined immunodeficiency mice. Human hepatocytes were used as positive controls. Tracking of the transplanted human cells could be achieved by in situ hybridization with alu probes. Cells with alu-positive nuclei stained positive for human albumin and glycogen. Both markers were negative before transplantation. However, cells with alu-positive nuclei did not show a hepatocyte-like morphology and did not express cytochrome P450 3A4, and this suggests that these cells represent a mixed cell type possibly resulting from partial transdifferentiation. Using antibodies specific for human albumin, we also observed a second human albumin-positive cell type that could be clearly distinguished from the previously described cells by its hepatocyte-like morphology. Surprisingly, these cells had a mouse and not a human nucleus which is explained by transdifferentiation of human cells. Although it has not yet been formally proven, we suggest horizontal gene transfer as a likely mechanism, especially because we observed small fragments of human nuclei in mouse cells that originated from deteriorating transplanted cells. Qualitatively similar results were obtained with all 4 human precursor cell types through different routes of administration with and without the induction of liver damage.


CONCLUSIONS
We observed evidence not for transdifferentiation but instead for a complex situation including partial differentiation and possibly horizontal gene transfer.
Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany. brulport@ifado.de
Marc
M
Brulport
Wiebke
W
Schormann
Alexander
A
Bauer
Matthias
M
Hermes
Carolin
C
Elsner
Friedrich Jakob
FJ
Hammersen
Walter
W
Beerheide
Dimitry
D
Spitkovsky
Wolfgang
W
Härtig
Andreas
A
Nussler
Lars Christian
LC
Horn
Jeanett
J
Edelmann
Oliver
O
Pelz-Ackermann
Jörg
J
Petersen
Manja
M
Kamprad
Marc
M
von Mach
Amelie
A
Lupp
Henryk
H
Zulewski
Jan G
JG
Hengstler
D000418:Albumins / Q000032:analysis; D000818:Animals; D002454:Cell Differentiation; D006801:Humans; D008099:Liver / Q000166:cytology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000737:chemistry / Q000166:cytology* / Q000502:physiology; D014183:Transplantation, Heterologous
D000418:Albumins