Downregulation of beta2-microglobulin in human cord blood somatic stem cells after transplantation into livers of SCID-mice: an escape mechanism of stem cells?
Adherently growing, non-hematopoietic somatic stem cells isolated from human cord blood were stained with the fluorescent dye PKH26 and transplanted into livers of SCID-mice to examine a possible cell fate transition. Already 7 days after transplantation stem cells were well integrated into the liver tissue. Human albumin that was not expressed by the stem cells before transplantation was detectable in the host's livers after injection of cord blood stem cells. Human alpha1-antitrypsin was detectable in stem cells already before transplantation and remained positive in the mouse liver. The most interesting observation in this study was the downregulation of human beta2-microglobulin (beta2M) in the stem cells after transplantation: beta2M is expressed constitutively in our cord blood stem cells. However, beta2M was no longer detectable by RT-PCR in all tissues where human albumin and alpha1-antitrypsin were expressed after stem cell transplantation. beta2M is known to participate as an integral part of the major histocompatibility complex. Absence of beta2M makes the residual heavy chain inactive as an antigen. Thus, downregulation of beta2M may represent an escape mechanism from killer-T cells and may be a molecular mechanism explaining the recently described "immunological blindness" [37] of stem cells. In contrast to the results obtained after direct injection of stem cells as a suspension, no consistent downregulation of beta2M was observed after transplantation of stem cells encapsulated in alginate beads to generate a compartment where stem cells are protected from the host's natural killer cells. No expression of human genes was observed after transplantation of human cord blood derived mononuclear cells (MNC) that were used as a negative control. In conclusion, we have shown that human cord blood somatic stem cells survive and are reprogrammed after transplantation into mouse livers, although a complete transdifferentiation to hepatocytes did not occur within 7 days, since some marker genes (GATA4 and alpha-fetoprotein) were still negative. Switching off expression of beta2M may be part of an intriguing and novel mechanism explaining why stem cells escape the host's immune system.
Beerheide
W
W
Kourion Therapeutics, Himmelgeister Str. 248, 40225 Düsseldorf, Germany. walter.beerheide@cytonet.de
von Mach
M A
MA
Ringel
M
M
Fleckenstein
C
C
Schumann
S
S
Renzing
N
N
Hildebrandt
A
A
Brenner
W
W
Jensen
O
O
Gebhard
S
S
Reifenberg
K
K
Bender
J
J
Oesch
F
F
Hengstler
J G
JG
D000368:Aged; D000418:Albumins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015536:Down-Regulation; D005312:Fetal Blood / Q000166:cytology*; D020868:Gene Silencing; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D012333:RNA, Messenger / Q000096:biosynthesis; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology; D015533:Transcriptional Activation; D023001:Transplantation Tolerance; D001613:beta 2-Microglobulin / Q000235:genetics / Q000378:metabolism*
D000418:Albumins; D012333:RNA, Messenger; D001613:beta 2-Microglobulin