Wnt signaling controls the fate of mesenchymal stem cells

Ling, Ling; Nurcombe, Victor; Cool, Simon M.

doi:10.1016/j.gene.2008.12.008

Cited by 372 publications

(336 citation statements)

References 114 publications

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“…To define the molecular basis of COUP-TFII regulation, we searched for potential COUP-TFII effectors with the ability to modulate MSC lineage allocation. Activation of the canonical Wnt cascade and its downstream targets governs the mesenchymal cell-fate program (27)(28)(29)(30)(31)(32)(33). We found that Wnt10b was up-regulated in COUP-TFII-deficient cells (Fig.…”

Section: Cre-ert2/+mentioning

confidence: 70%

Nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) modulates mesenchymal cell commitment and differentiation

Xie¹,

Qin²,

Lin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The mesenchymal cell is a multipotent stem cell with the capacity to give rise to multiple cell types such as adipocytes, osteoblasts, chondrocytes, and myocytes. However, the molecular events responsible for their lineage specification and differentiation remain obscure. Here we show that inactivation of chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), a member of the nuclear receptor superfamily, in mesenchymal progenitors favors osteoblast and myoblast development while simultaneously impairing adipogenic and chondrogenic programs. During mouse embryogenesis, COUP-TFII protein is highly detected in the mesenchymal compartment and is involved in mesoderm tissue formation. Ablation of COUP-TFII in mice led to higher bone density, increased muscle mass, and suppression of cartilage and fat formation. We further demonstrate that COUP-TFII directs the plasticity of mesenchymal precursors primarily through the combined modulation of Wnt signaling, Runx2 activity, as well as PPARγ and Sox9 expression. Together, our results provide insight into the mechanisms whereby a single nuclear receptor can fine-tune the lineage-specific differentiation of a progenitor cell.

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Section: Cre-ert2/+mentioning

confidence: 70%

Nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) modulates mesenchymal cell commitment and differentiation

Xie¹,

Qin²,

Lin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…(11,12) Wnt signaling cascades have been demonstrated to play different roles at various stages of bone development. (13) Wnt signaling is broadly classified into the b-catenin-dependent canonical and b-catenin-independent noncanonical pathways. The involvement of canonical Wnt signaling in the commitment, proliferation, and function of osteoblasts has been studied extensively.…”

Section: Introductionmentioning

confidence: 99%

“…Noncanonical Wnt signaling involves many distinct signaling cascades and effectors, including protein kinase C, (24) Dvl, (25,26) Rho, (27)(28)(29) c-jun N-terminal kinase, (30) and calcium/ calmodulin-dependent kinase II (CaMKII). (13,(31)(32)(33) Nemo-like kinase (NLK) and the nuclear factor of activated T cells (NF-AT) are well characterized effectors of Ca 2þ -dependent noncanonical Wnt signaling. (34)(35)(36) NLK phosphorylates TCF/LEF1 and inhibits its binding to b-catenin, thus antagonizing canonical Wnt signaling.…”

Section: Introductionmentioning

confidence: 99%

Mechanical stretching induces osteoprotegerin in differentiating C2C12 precursor cells through noncanonical Wnt Pathways

Chen

et al. 2010

Journal of Bone and Mineral Research

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Mechanical loading is known to be important for maintaining the formation and resorption rates of bone. To study the mechanisms by which mechanical loading regulates osteogenesis, we investigated the role of the Wnt pathway in C2C12 cells committed to osteogenic differentiation in response to cyclic mechanical stretching. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL to inhibit osteoclastogenesis and resorption of bone. Our results demonstrate that stretching leads to a sustained increase in OPG expression in C2C12 cells. The expression of osteogenic marker genes, such as osteocalcin and alkaline phosphatase, was transiently decreased by stretching at 24 hours and returned to control levels at 48 hours. The addition of inhibitors of the canonical Wnt/b-catenin pathways, such as the secreted FZD-related peptide sRFP2, as well as siRNA-mediated knockdown, did not inhibit the effect of stretching on OPG expression. In contrast, treatment with inhibitors of noncanonical Wnt signaling, including KN93, and siRNA for Nemo-like kinase (NLK) blocked most of the mechanical inductive effect on OPG. Furthermore, stretching-induced OPG production in the culture medium was able to inhibit the osteoclast formation of bone marrow macrophages. These results suggest that mechanical stretching may play an important role in bone remodeling through the upregulation of OPG and that the mechanical signaling leading to OPG induction involves the noncanonical Wnt pathway. ß

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“…In contrast, noncanonical Wnt signaling does not operate through b-catenin. 33 In bone, the role of canonical Wnt signaling is debated and has both been seen to promote proliferation and differentiation, as well as to inhibit proliferation via Wnt3a. 34,35 One study suggests that this effect may be concentration-dependent, with low doses of Wnt stimulating proliferation and high doses of Wnt inhibiting it.…”

Section: Signals Regulating Mscs During Bone Regenerationmentioning

confidence: 99%