Activating PIK3CA Mutations of Adipose-derived Stem Cells Drive Mutant-like Phenotypes of Wild-type Cells in Macrodactyly

Background Pathological adipose proliferation is one of characteristic manifestations of macrodactyly. Although PIK3CA gain-of-function mutations are known to impact adipose-derived stem cells (ADSCs) in macrodactyly, their effects on adjacent wild-type cells are poorly understood. Methods We utilized conditioned medium and transwell systems to investigate the influence of macrodactylous adipose-derived stem cells (Mac-ADSCs) on normal ADSCs, fibroblasts (FBs), and vascular endothelial cells (VECs). Cellular behavior changes were assessed by proliferation, migration, invasion, adipogenesis, and angiogenesis assays. RNA sequencing, cytokine array analysis, and western blotting were used to explore the differential secretion of cytokines, and the pathways activated. Results Our research demonstrated that Mac-ADSCs enhance the proliferation, migration, invasion, adipogenesis, and angiogenesis of wild-type ADSCs, FBs and VECs, attributable to the activating mutation in PIK3CA. This enhancement is predominantly mediated through the direct action of various paracrine secreted cytokines. Meanwhile, the differentially secreted cytokines could over-activate PI3K-AKT signaling pathway in wild-type cells. BYL-719, a potent PIK3CA inhibitor, emerges as a potential therapeutic option for reversing the paracrine effects induced by Mac-ADSCs. Conclusions The activating PIK3CA mutation modify the paracrine characteristics of Mac-ADSCs, inducing secretion of cytokines that drive adjacent wild-type cells to exhibit mutant-like phenotypes. Targeting PIK3CA could be a viable therapeutic option for macrodactyly, particularly in cases where paracrine signaling contributes to disease progression.