Cross-talk between Wnt signaling pathways in human mesenchymal stem cells leads to functional antagonism during osteogenic differentiation.
Wnt signaling is involved in developmental processes and in adult stem cell homeostasis. This study analyzes the role(s) of key Wnt signaling mediators in the maintenance and osteogenesis of mesenchymal stem cells (MSCs). We focus specifically on the involvement of low-density lipoprotein-related protein 5 (LRP5), T-cell factor 1 (TCF1), and Frizzled (Fz) receptors, in the presence or absence of exogenous, prototypical canonical (Wnt3a), and non-canonical (Wnt5a) Wnts. In undifferentiated MSCs, LRP5 and TCF1 mediate canonical Wnt signal transduction, leading to increased proliferation, enhanced synergistically by Wnt3a. However, LRP5 overexpression inhibits osteogenic differentiation, further suppressed by Wnt3a. Wnt5a does not affect cell proliferation but enhances osteogenesis of MSCs. Interestingly, Wnt5a inhibits Wnt3a effects on MSCs, while Wnt3a suppresses Wnt5a-mediated enhancement of osteogenesis. Flow cytometry revealed that LRP5 expression elicits differential changes in Fz receptor profiles in undifferentiated versus osteogenic MSCs. Taken together, these results suggest that Wnt signaling crosstalk and functional antagonism with the LRP5 co-receptor are key signaling regulators of MSC maintenance and differentiation.
Baksh
Dolores
D
Department and Health and Human Services, Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Boland
Genevieve M
GM
Tuan
Rocky S
RS
D000368:Aged; D002454:Cell Differentiation; D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D051157:Frizzled Receptors / Q000378:metabolism; D017930:Genes, Reporter; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008875:Middle Aged; D008954:Models, Biological; D015675:Osteocalcin / Q000235:genetics; D010012:Osteogenesis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein; D060508:Wnt3 Protein; D060509:Wnt3A Protein
D017077:Culture Media, Conditioned; D051157:Frizzled Receptors; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D011518:Proto-Oncogene Proteins; C555510:WNT3A protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D015675:Osteocalcin