Fig. 8

Schematic diagram of the extracellular and intracellular mechanisms of hAMSCs-derived DKK-3, DKK-1, and IGFBP3 effect on the activation of HSCs. A Activated HSCs: The Wnt/β-catenin signaling pathway is in the activated state (on). The Wnts act on the FZD/LRP complex on the surfaces of HSCs. Wnt-Fzd and LRP coordinate the Dvl activation, leading to the recruitment of axin to the plasma membrane. Activated Dvl then dissociates the multiprotein complex consisting of axin, APC, CK1α, and GSK3β, resulting in the inactivation of GSK3β, which can no longer phosphorylate the β-catenin. Excess free β-catenin translocates to the nucleus, causing activation of HSCs. The IGF-1R/PI3K/AKT signaling pathway is also activated in the activated state. B Quiescent HSCs: hAMSCs-secreted Dkk-1 and Dkk-3, two antagonists of Wnt/β-catenin signaling pathway, are capable of suppressing the binding of Wnt ligands to FZD receptors and LRP co-receptors. β-catenin is assembled and phosphorylated by the destruction complex to be further ubiquitinated (Ub) for proteasomal degradation. IGFBP-3 secreted by hAMSCs can inhibit IGF1R/PI3K/AKT signaling by sequestering IGF1, resulting in the activation of GSK3β and GSK3β signaling.