FoxA2 regulates the type II collagen–induced nucleus pulposus–like differentiation of adipose‐derived stem cells by activation of the Shh signaling pathway

Abstract

Adipose tissue-derived stem cell (ADSC)-based therapy is promising for the treatment of intervertebral disc (IVD) degeneration, but the difficulty in inducing nucleus pulposus (NP)-like differentiation limits its clinical applications. Forkhead box (Fox)-A2 is an essential transcription factor for the formation of a normal NP. We demonstrated that type II collagen stimulates NP-like differentiation of ADSCs, partly by increasing the expression of FoxA2. We constructed FoxA2-overexpressing and -knockdown ADSCs by using lentiviral vectors. FoxA2 overexpression significantly enhanced NP-specific gene expression and the synthesis of glycosaminoglycan and collagen, whereas FoxA2 knockdown decreased NP-like differentiation and the expression of aggrecan and collagen II. The enhanced NP-like differentiation related to FoxA2 overexpression was partially rescued by an Shh signaling pathway inhibitor. In addition, FoxA2 inhibited the expression of Itg-α2 and further promoted NP-like differentiation induced by type II collagen. Furthermore, FoxA2-overexpressing ADSCs combined with type II collagen hydrogels promoted regeneration of degenerated NP in vivo. Our findings suggest that FoxA2 plays an essential role in the NP-like differentiation of ADSCs by activating the Shh signaling pathway.-Zhou, X., Ma, C., Hu, B., Tao, Y., Wang, J., Huang, X., Zhao, T., Han, B., Li, H., Liang, C., Chen, Q., Li, F. FoxA2 regulates the type II collagen-induced nucleus pulposus-like differentiation of adipose-derived stem cells by activation of the Shh signaling pathway.

Injectable kartogenin and apocynin loaded micelle enhances the alleviation of intervertebral disc degeneration by adipose-derived stem cell

“…Human ADSCs are multipotent cells characterized by their ability to differentiate into adipocytes, chondrocytes, and osteoblasts [ 42 ]. Previous studies have demonstrated the beneficial effect of mesenchymal stem cells on intervertebral disc degeneration [ [43] , [44] , [45] ]. But there are still many problems between the microenvironment and transplanted cells.…”

Biomaterials-Induced Stem Cells Specific Differentiation Into Intervertebral Disc Lineage Cells

“…Similarly, Shh protein expression level has also been shown an increase when crosslinked scaffolds promoted ADSC proliferation and differentiation into NP-like cells, indicating that the activation of the Shh signaling pathway might play a regulatory role in directional differentiation (Zhou et al, 2018b). In addition, NP-like cell differentiation induced by Collagen type II is related to FoxA2 overexpression and can be rescued by a Shh signaling pathway inhibitor (Zhou et al, 2018a).…”

“…When ADSCs were embedded in Collagen type II hydrogels compared with Collagen type I hydrogels, an upregulation of Collagen type IIA, collagen type IIB and aggrecan gene expressions and stronger alcian blue staining were observed, indicating a more pronounced differentiation of ADSCs to the cartilage lineage (Lu et al, 2008). Collagen type II alone has been shown to induce ADSC differentiation into NP-like cells (Zhou et al, 2018b), which was related to FoxA2 overexpression (Zhou et al, 2018a). Moreover, Collagen type II combined with other natural components and crosslinkers, such as chondroitin sulfate (Zhou et al, 2018c), hyaluronan (Calderon et al, 2010), genipin (Zhou et al, 2018b), N,N-(3-dimethylaminopropyl)-N -ethylcarbodiimide and N-hydroxysuccinimide (EDAC/NHS) , to modify its porosity and other micromechanical properties has also been shown to exert an improved effect on stem cell proliferation and directional differentiation.…”

“…Yes-associated protein (YAP) has been shown to involve in differentiation of AFSCs. Outer AF phenotypic marker genes increased, when AFSCs were cultured on PECUU scaffolds with higher stiffness or greater fiber size, while YAP was translocated FIGURE 6 | Signaling pathways associated with biomaterials-induced IVD cells directional differentiation (Dahia et al, 2012;Blanquer et al, 2017;Zhou et al, 2018a;Chen et al, 2019b;Chu et al, 2019). SCs, stem cells.…”

“…Cytomegalovirus US2/US3 gene was introduced into ADSCs to generate a ADSCs with decreased MHC I protein, thus reducing the activation of T-cells of recipients (Ren et al, 2012). Moreover, engineering MSCs, such as FoxA2-overexpression (Zhou et al, 2018a), is a potential approach to achieve specific differentiation without the supplement of growth factors (Liao, 2016), thus engineered MSCs may be ideal sources of cell delivery vehicles.…”