Fig. 8

Proposed Wnt, VEGF/PDGF, and TGF signaling pathways mediating self-renewal and cell cycle arrest in pMSCs. In XM, the Wnt protein binds to the Frizzled receptor, keeping the Wnt pathway active. This destabilizes the destruction complex (DVL/AXIN/APC/GSK3β/CK1) and allows β-catenin to promote the expression of self-renewal genes in the nucleus. Additionally, growth factors like VEGF and PDGF play a role in pMSC proliferation in XM by phosphorylating their respective receptors. This recruits the adaptor protein GRB2 and the nucleotide exchange factor SOS, which activate RAS, RAF, MEK, and ERK in sequence. Phosphorylated ERK enters the nucleus and activates the transcription of cell proliferation genes such as c-MYC. Alternatively, ERK activates RSK, which then activates proliferation genes. In FM, PI3K is activated, leading to an increase in PTEN and PDK1 expression, which activates AKT. Activated AKT presumably phosphorylates MDM2, modulating p53 activity responsible for senescence gene expression. Senescence is gradually induced by TGFβ interaction with TGFβR, which phosphorylates SMAD2/3, moving to the nucleus with SMAD4 to turn on genes involved in cell cycle arrest