Wnt signalling in mouse mesenchymal stem cells: impact on proliferation, invasion and MMP expression.
Based on the capacity of mesenchymal stem cells (MSC) to differentiate into multiple cell types in vitro and in vivo, MCS may be a suitable source for cell therapy and regeneration strategies. A prerequisite for effective clinical applications of human MSC (hMSC) is a profound knowledge of signal transduction cascades that mediate processes like proliferation, targeted migration and differentiation. Recently, we identified the canonical Wnt signal transduction pathway as a key player in hMSC proliferation and invasion. To evaluate whether those findings are transferable to the equivalent counterparts in mice, we studied important steps in the wingless/int-1 (Wnt) signal transduction pathway in mouse MSC (mMSC) and mMSC carrying a T cell specific transcription factor (TCF)/lymphoid enhancer binding factor (LEF)-reporter transgene. We found that the induction of the canonical Wnt pathway resulted in the up-regulation of the known Wnt target gene cyclin D1, closely associated with an enhanced proliferation capacity of mMSC. Interestingly, the expression of the Wnt target gene membrane type 1-matrix metalloproteinase (MT1-MMP) was diminished in mMSC upon Wnt3a stimulation, which came along with an impaired invasion. In line with these findings, MMP-2 and MMP-9 expression levels in mMSC were also decreased after Wnt3a treatment. In contrast, inhibition of Wnt signalling by the knockdown of the transcriptional activator beta-catenin resulted in an up-regulation of MT1-MMP and mMSC invasion. By comparing these findings with the settings in hMSC, major differences in Wnt-regulated MMP expression were observed in mMSC. Thus, our data advice caution when mouse model systems represent the pre-clinical validation of MSC-mediated therapeutical approaches.
Division of Clinical Chemistry and Clinical Biochemistry, Department of Surgery, Ludwig-Maximilians-University of Munich, Munich, Germany.
Marisa
M
Karow
Division of Clinical Chemistry and Clinical Biochemistry, Department of Surgery, Ludwig-Maximilians-University of Munich, Munich, Germany.
Tanja
T
Popp
Division of Clinical Chemistry and Clinical Biochemistry, Department of Surgery, Ludwig-Maximilians-University of Munich, Munich, Germany.
Virginia
V
Egea
Division of Clinical Chemistry and Clinical Biochemistry, Department of Surgery, Ludwig-Maximilians-University of Munich, Munich, Germany.
Christian
C
Ries
Division of Clinical Chemistry and Clinical Biochemistry, Department of Surgery, Ludwig-Maximilians-University of Munich, Munich, Germany.
Marianne
M
Jochum
Division of Clinical Chemistry and Clinical Biochemistry, Department of Surgery, Ludwig-Maximilians-University of Munich, Munich, Germany.
Peter
P
Neth
D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D017931:DNA Primers; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
D017931:DNA Primers; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D020782:Matrix Metalloproteinases