Enhanced Chondrogenic Differentiation of Human Umbilical Cord Wharton's Jelly Derived Mesenchymal Stem Cells by GSK-3 Inhibitors

Abstract

Articular cartilage is an avascular, alymphatic, and aneural system with very low regeneration potential because of its limited capacity for self-repair. Mesenchymal stem cells (MSCs) are the preferred choice for cell-based therapies. Glycogen synthase kinase 3 (GSK-3) inhibitors are compounds that can induce the Wnt signaling pathway, which is involved in chondrogenesis and cartilage development. Here, we investigated the influence of lithium chloride (LiCl) and SB216763 synergistically with TGF-β3 on chondrogenic differentiation in human mesenchymal stem cells derived from Wharton’s jelly tissue (hWJ-MSCs). hWJ-MSCs were cultured and chondrogenic differentiation was induced in monolayer and pellet experiments using chondrogenic medium, chondrogenic medium supplemented with LiCl, or SB216763 for 4 weeks. After in vitro differentiation, cultured cells were examined for the expression of Sox9, ACAN, Col2a1, and β-catenin markers. Glycosaminoglycan (GAG) accumulation was also examined by Alcian blue staining. The results indicated that SB216763 was more effective than LiCl as evidenced by a higher up-regulation of the expression of cartilage-specific markers, including Sox9, ACAN, Col2a1 as well as GAG accumulation. Moreover, collagen type II expression was strongly observed in cells cultured in the chondrogenic medium + SB216763 as evidenced by western blot analysis. Both treatments appeared to mediate the Wnt signaling pathway by up-regulating β-catenin gene expression. Further analyses showed that all treatments suppressed the progression of chondrocyte hypertrophy, determined by decreased expression of Col10a1 and Runx2. These results indicate that LiCl and SB216763 are potential candidates for further in vivo therapeutic trials and would be of great importance for cartilage regeneration.

The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models

“…The selective PI3Kα inhibitor BYL719 significantly reduced cell viability and colony formation in all NET cell lines investigated, with the highest sensitivity in BON-1, followed by H727 cells, and a much lower sensitivity in QGP-1 cells. The highest sensitivity of BON-1, followed by H727 cells, might be due to stronger BYL719-induced apoptosis as a potential consequence of GSK3 inhibition and tumor cell re-differentiation with significant SSTR1/2 up-regulation, in contrast to lower apoptosis induction, absent GSK3 inhibition and absent re-differentiation in QGP-1 cells [ 71 , 72 , 85 , 101 , 106 , 107 ]. Thus, BYL719 may sensitize neuroendocrine tumor cells to therapy with somatostatin analogs or PRRT, depending on the specific cell line.…”

Uptake of magnetic nanoparticles for adipose-derived stem cells with multiple passage numbers

“…These sources must be safe, biocompatible, and free from any ethical dispute. Mesenchymal stem cells (MSCs) are typically considered to be capable of differentiation into vascular endothelial cells [5], osteoblasts [6], chondrocytes [7], and adipocytes [8]. The sources of MSCs are diverse and those derived from adipose tissue have immune exemption characteristics [9] and the ability to inhibit activated lymphocyte proliferation in allografts [10].…”

The LncRNA ZBED3-AS1 induces chondrogenesis of human synovial fluid mesenchymal stem cells

“…Additionally, it has been reported [20] [27,28] that the combination of TGF-b and Wnt signaling stimulates the chondrogenic differentiation of human marrow stromal cells, and the canonical Wnt signaling pathway promotes chondrocyte differentiation in a sox9-dependent manner. GSK-3 inhibitors can induce the wnt signaling pathway and promote the chondrogenic differentiation of hWJ-MSCs in the presence of TGF-b3, without inducing chondrocyte hypertrophy [29]. In the overexpression group, we detected relatively high levels of zbed3, sox 9, and col II expression, and these high expression levels could be reversed by treatment with the wnt-inhibitor DKK-1.…”