Effects of Wnt Signaling on Proliferation and Differentiation of Human Mesenchymal Stem Cells

Abstract

Mesenchymal stem cells are pluripotent cells from bone marrow, which can be differentiated into the osteogenic, chondrogenic, and adipogenic lineages in vitro and are a source of cells in bone and cartilage tissue engineering. An improvement in current tissue-engineering protocols requires more detailed insight into the molecular cues that regulate the distinct steps of osteochondral differentiation. Because Wnt signaling has been widely implicated in mesenchymal differentiation, we analyzed the role of Wnt signaling in human mesenchymal stem cell (hMSC) biology by stimulation of the pathway with lithium chloride and Wnt3A-conditioned medium. We demonstrate a role for low levels of Wnt signaling in proliferation of uncommitted hMSCs and confirm that Wnt signaling controls osteoprogenitor proliferation. On the other hand, at high Wnt levels we observed a block in adipogenic differentiation and an increase in the expression of alkaline phosphatase, suggesting a role in the initiation of osteogenesis. The results of this study suggest that bone tissue engineering could benefit from the activation of critical levels of Wnt signaling at defined stages of differentiation. Moreover, our data suggest that hMSCs provide a valid in vitro model to study the role of Wnt signaling in mesenchymal biology.

Wnt signaling and skeletal development

“…In contrast to the data in the cell types described above, Wnt3a was reported to have an adverse effect on ALP expression in human mesenchymal stem cell osteogenic cultures [100][101][102] -the earlier the treatment with Wnt3a conditional medium, the stronger the inhibition of mineralization [100]. However, one report showed that addition of Wnt3a in conditional medium to mouse bone marrow stromal cell osteogenic culture led to increased mineralization [77].…”

“…The LiCl dose dependently induced ALP activity (from 0.1 mM to 20 mM) [95] and ALP mRNA expression in C3H10T1/2 [87,93], ST2 [87], and C2C12 [87] cells. However, it was shown that 4 mM LiCl either had no apparent effect on ALP level (4 mM) in human mesenchymal stem cells [102], or reduced the BMP2-induced osteoblast differentiation (in C2C12 cells and human mesenchymal stem cells) [106] and dexamethasone-induced osteoblast differentiation [100]. LiCl is able to stimulate ALP activity in murine embryonic mesenchymal stem cells but not in calvaria cells [56].…”

Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation

“…Studies using various in vitro systems have suggested that the Wnt/b-catenin pathway promotes osteoblastogenesis and chondrogenesis. (12,(24)(25)(26) In contrast, other studies have reported that Wnts either enhance the proliferation and/or suppress the differentiation of mesenchymal progenitor cells, (27)(28)(29) preosteoblasts, (30) or cementoblasts. (31) Other studies in Wnt signaling revealed a more complex transduction network than previously thought.…”

Modeling sarcomagenesis using multipotent mesenchymal stem cells

“…In addition, WNT signaling also regulates the proliferation, differentiation and invasion capacity of hMSCs [48,49]. While these functions exerted by the WNT pathway may be useful in tissue regeneration, an aberrant or inadequate activation of this pathway may deregulate the balance between proliferation, differentiation and apoptosis, leading to malignant transformation.…”