Fibroblast growth factor 2 and platelet-derived growth factor, but not platelet lysate, induce proliferation-dependent, functional class II major histocompatibility complex antigen in human mesenchymal stem cells.
OBJECTIVE
To document the specificity and the mechanism of induction of a novel class II major histocompatibility complex (MHC) antigen by mitogenic growth factors in human mesenchymal stem cells (MSCs) expanded in vitro for translational applications.


METHODS
Expression of class II MHC molecules was measured in human MSCs and differentiated cells expanded in the presence of fibroblast growth factor 2 (FGF-2), platelet-derived growth factor BB (PDGF-BB), human platelet lysate, or interferon-γ (IFNγ). The roles of cell proliferation and growth factor-induced signaling pathways were investigated as well as the class II MHC assembly machinery and functional capacity.


RESULTS
FGF-2 and, to a lesser extent, PDGF-BB induced in adult human MSCs the expression of HLA-DR (normally induced by inflammatory cytokines), which was able to stimulate CD4+ T cells via superantigen binding. In contrast to IFNγ, FGF induced HLA-DR expression only in human MSCs proliferating under its mitogenic effect and not in mouse MSCs or in differentiated human cells. Although it induced cell proliferation, human platelet lysate did not cause HLA-DR expression in human MSCs. HLA-DR expression occurred following FGF-specific binding to its receptor(s), mainly FGF receptor 1, without inducing IFNγ or tumor necrosis factor α expression. Both MAPK/ERK-1/2 and phosphatidylinositol 3-kinase/Akt controlled cell proliferation and HLA-DR expression, but only MAPK/ERK-1/2 controlled the induction of the class II MHC transcription activator protein CIITA, the major determinant of HLA-DR transcription.


CONCLUSIONS
The induction of functional HLA-DR in proliferating progenitor MSCs is a property of human MSCs that have been expanded with mitogenic growth factors. This has potential biologic significance in the regulation and/or protection of progenitor cell subpopulations under sustained mitogenic proliferation and needs to be taken into account when expanding MSCs for use in in vivo applications.
Bocelli-Tyndall
Chiara
C
University Hospital Basel and University of Basel, Basel, Switzerland.
Zajac
Paul
P
Di Maggio
Nunzia
N
Trella
Emanuele
E
Benvenuto
Federica
F
Iezzi
Giandomenica
G
Scherberich
Arnaud
A
Barbero
Andrea
A
Schaeren
Stefan
S
Pistoia
Vito
V
Spagnoli
Giulio
G
Vukcevic
Mirko
M
Martin
Ivan
I
Tyndall
Alan
A
D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011810:Quinoxalines / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism
C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D002867:Chromones; D005419:Flavonoids; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009025:Morpholines; D009687:Nuclear Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor; D011810:Quinoxalines; D045162:Thiazolidinediones; D015534:Trans-Activators; D016222:Fibroblast Growth Factor 2; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one