WNT3A modulates chondrogenesis via canonical and non-canonical Wnt pathways in MSCs 

Abstract

The multilineage commitment of mesenchymal stem cells (MSCs) is controlled via unknown mechanisms. In this study, we investigated the regulation of the differentiation of MSCs into chondrocytes via the Wnt signaling pathway. Overexpression of WNT3A in MSCs activated both the canonical and non-canonical Wnt pathways, which were responsible for different WNT3A-induced outcomes. WNT3A promoted MSC proliferation via the ß-catenin-mediated canonical Wnt pathway, and inhibited chondrogenesis of MSCs via the calcium/calmodulin-dependent kinase II (CaMKII)-mediated non-canonical Wnt pathway. Interestingly, blockade of the canonical Wnt pathway by Dickkopf-related protein 1 exerted a synergistic effect on the inhibition of chondrogenesis of MSCs, while blockade of the non-canonical Wnt pathway by KN93 also exerted a synergistic effect on MSCs proliferation. These results suggest that the WNT3A-activated canonical and non-canonical pathways counteract each other in the setting of MSCs. This study provides evidence for the delicate regulation of the Wnt signaling cascade during chondrogenesis of MSCs, and suggests that genetic manipulation of the Wnt pathway may offer a powerful vehicle for modulating MSC differentiation in stem-cell-based cartilage repair.

Human iPSC-derived MSCs (iMSCs) from aged individuals acquire a rejuvenation signature

“…Interestingly, we found SerpinE1, thrombospondin-1, IGFBP3, endoglin, and angiogenin to be abundantly secreted in fetal MSCs and iMSCs. The described role of SerpinE1, thrombospondin-1, and endoglin in wound healing [78–80] indicate a putative fetal-like feature of wound healing properties of iMSCs in vivo [81, 82]. Our analyses revealed that aMSCs compared to fMSCs and iMSC secrete a reduced repertoire of cytokines and at significantly lower levels.…”

Macrophages promote epithelial proliferation following infectious and non-infectious lung injury through a Trefoil factor 2-dependent mechanism

“…However, comparison of RNA transcripts between WT and TFF2 −/− Mφ that were both exposed to damaged MTEC revealed that C amkk2b expression was significantly (>2-fold) under-represented in TFF2 −/− Mφ (Supplementary Figure 5b). Because C amkk2b is implicated in the calcium dependent pathway for Wnt glycoprotein expression 34, 35 , which in turn regulates multiple aspects of epithelial cell biology, we reasoned that Mφ-derived TFF2 may promote epithelial repair, at least partially, via regulating Wnt expression.…”

The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche

“…Using phosphospecific antibodies, we observed that Ser33/37/Thr41-phospho β-catenin (inactive) is totally absent in MSC cell lysate, thus suggesting that the Wnt/β-catenin is fully active in MSCs (Takam Kamga et al, 2016b;Wang et al, 2019). The requirement of a functional β-catenin-independent Wnt signaling, such as Wnt/Ca 2+ , Wn/Jnk, Wnt/Ryk, Wnt/Ror2, was also described in MSCs (Qiu et al, 2011;Qu et al, 2013;Jeong et al, 2020). Overall, the activation of the pathway plays a critical role in cell fate decisions, notably for MSC proliferation, self-renewal and differentiation.…”

“…One key mechanism of the suppressive role of Wnt/β-catenin on adipogenesis is the reduced expression of adipogenic transcription factors CCAAT/enhancer binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) (Ross et al, 2000;Yuan et al, 2016). However, the use of Wnt/β-catenin inhibitors, such as Quercitin, reduce MSC proliferation and multipotency by favoring their osteogenic commitment and inhibiting both the chondrogenic and the adipogenic differentiation (Qu et al, 2013;Narcisi et al, 2015;Jothimani et al, 2020;Volleman et al, 2020). This model failed to explain the positive contribution of canonical Wnt in bone homeostasis in vivo (Wagner et al, 2020).…”