Role of FOXC1 in regulating APSCs self-renewal via STI-1/PrP^C signaling

Abstract

Forkhead box protein C1 (FOXC1) is known to regulate developmental processes in the skull and brain. <b>Methods</b>: The unique multipotent arachnoid-pia stem cells (APSCs) isolated from human and mouse arachnoid-pia membranes of meninges were grown as 3D spheres and displayed a capacity for self-renewal. Additionally, APSCs also expressed the surface antigens as mesenchymal stem cells. By applying the FOXC1 knockout mice and mouse brain explants, signaling cascade of FOXC1-STI-1-PrP^C was investigated to demonstrate the molecular regulatory pathway for APSCs self-renewal. Moreover, APSCs implantation in stroke model was also verified whether neurogenic property of APSCs could repair the ischemic insult of the stroke brain. <b>Results</b>: Activated FOXC1 regulated the proliferation of APSCs in a cell cycle-dependent manner, whereas FOXC1-mediated APSCs self-renewal was abolished in FOXC1 knockout mice (<i>FOXC1^-/-</i> mice). Moreover, upregulation of STI-1 regulated by FOXC1 enhanced cell survival and self-renewal of APSCs through autocrine signaling of cellular prion protein (PrP^C). Mouse brain explants STI-1 rescues the cortical phenotype <i>in vitro</i> and induces neurogenesis in the <i>FOXC1</i>^-/- mouse brain. Furthermore, administration of APSCs in ischemic brain restored the neuroglial microenvironment and improved neurological dysfunction. <b>Conclusion</b>: We identified a novel role for FOXC1 in the direct regulation of the STI-1-PrP^C signaling pathway to promote cell proliferation and self-renewal of APSCs.