Signal transducer and activator of transcription 3-A key molecular switch for human mesenchymal stem cell proliferation.
Human bone marrow mesenchymal stem cells are multipotent cells with enormous potential for cellular therapies. Identifying those mediators that induce human bone marrow mesenchymal stem cell proliferation and elucidating the signaling networks involved will encourage clinical efforts exploiting such cells. Here, we demonstrate that platelet-derived growth factor-BB and basic fibroblast growth factor induce human bone marrow mesenchymal stem cell proliferation. Platelet-derived growth factor-BB induced human bone marrow mesenchymal stem cell proliferation via complete activation of the Janus-activated kinase-signal transducers and activators of transcription cascade, inducing signal transducer and activator of transcription 3 tyrosine and serine phosphorylation as well as Janus-activated kinase 2 tyrosine phosphorylation. Janus-activated kinase 2 was required for signal transducer and activator of transcription 3 tyrosine phosphorylation, whereas the extracellular signal-regulated kinase 1/2 mediated signal transducer and activator of transcription 3 serine phosphorylation in response to platelet-derived growth factor-BB. Furthermore, platelet-derived growth factor-BB was shown to promote nuclear translocation of signal transducer and activator of transcription 3. By contrast, basic fibroblast growth factor-stimulated human bone marrow mesenchymal stem cell proliferation was mediated via the extracellular signal-regulated kinase 1/2 pathway without involvement of the Janus-activated kinase-signal transducers and activators of transcription cascade. Importantly, platelet-derived growth factor-BB and basic fibroblast growth factor induced human bone marrow mesenchymal stem cell proliferation without affecting their osteogenic differentiation potential. Together, our study highlights the role of several growth factors in human bone marrow mesenchymal stem cell proliferation and the signaling pathways involved in the process. This information is crucial for achieving a better control over the human bone marrow mesenchymal stem cell expansion process.
Levy
Oren
O
Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel. levyor@bgu.ac.il
Dvir
Tal
T
Tsur-Gang
Orna
O
Granot
Yosef
Y
Cohen
Smadar
S
D000818:Animals; D000077214:Becaplermin; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin; D004815:Epidermal Growth Factor; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3