In vitro and in vivo immunosuppressive characteristics of hepatocyte growth factor-modified murine mesenchymal stem cells.
BACKGROUND
Previous data have proven that hepatocyte growth factor (HGF) is able to maintain the survival of mesenchymal stem cells (MSCs), rendering HGF gene modification as an optional strategy for MSC therapy. However, the question about whether gene-transferred MSCs (MSC/HGFs) exhibit more potent immunosuppressive activity remains elusive.


METHODS
Murine MSCs were isolated, culture-expanded and transfected by an adenovirus carrying human HGF cDNA (Ad-HGF). The transfection efficiency was evaluated by measuring HGF concentrations in the culture supernatants. An MHC-incompatible skin grafting model (C57BL-->BALB/c) was used to observe if MSC/HGF transfusion could prolong the survival time of skin transplants compared to MSCs. Furthermore, their inhibitory effects on the proliferation of T lymphocytes elicited by Con A and the activation of CD11b+ cells in mixed lymphocyte reaction were compared with carboxyfluorescein diacetate succinmidyl ester labeling and flow cytometric techniques.


RESULTS
Ad-HGF was able to transfect mouse MSCs at high efficiency and administration of MSC/HGFs remarkably prolonged the mean survival time of skin grafts (16.73 +/- 0.57 days, p<0.01), compared with mice receiving MSCs (14.27 +/- 0.63 days), or saline (10.92 +/- 0.73 days). However, the presence of MSC/HGFs exhibited little additive impact on the suppression of T lymphocyte proliferation and activation of CD11b-positive and -negative cells in comparison with MSCs, though the inhibitory effects were evidently greater than with NIH3T3 cells and their Ad-HGF-modified counterparts.


CONCLUSIONS
MSC/HGFs inhibit in vitro immune responses in a pattern similar to MSCs, but this gene modification might have beneficial effects for transplanted cells and damaged tissue.
Beijing 307 Hospital, The Academy of Military Medical Sciences, Beijing, People's Republic of China.
Li
L
Bian
Zi-Kuan
ZK
Guo
Heng-Xiang
HX
Wang
Jin-Song
JS
Wang
Hua
H
Wang
Qing-Fang
QF
Li
Yue-Feng
YF
Yang
Feng-Jun
FJ
Xiao
Cu-Tse
CT
Wu
Li-Sheng
LS
Wang
D000818:Animals; D018845:CD11 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000494:pharmacology; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous
D018845:CD11 Antigens; D007166:Immunosuppressive Agents; D008934:Mitogens; D017228:Hepatocyte Growth Factor