1. Translational Medicine Research Center, Drug Development Center and Department of Neurology, China Medical University & Hospital, Taichung, Taiwan
2. Department of Neurosurgery, Taichung Veterans General Hospital, Taichung, Taiwan
3. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
4. Graduate Institute of Biomedical Science and Drug Development Center, China Medical University, Taichung, Taiwan
5. Department of Occupational Therapy, Asia University, Taichung, Taiwan
*These authors contributed equally to this article.
Forkhead box protein C1 (FOXC1) is known to regulate developmental processes in the skull and brain.
Methods: 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-PrPC 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.
Results: 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 (FOXC1-/- mice). Moreover, upregulation of STI-1 regulated by FOXC1 enhanced cell survival and self-renewal of APSCs through autocrine signaling of cellular prion protein (PrPC). Mouse brain explants STI-1 rescues the cortical phenotype in vitro and induces neurogenesis in the FOXC1-/- mouse brain. Furthermore, administration of APSCs in ischemic brain restored the neuroglial microenvironment and improved neurological dysfunction.
Conclusion: We identified a novel role for FOXC1 in the direct regulation of the STI-1-PrPC signaling pathway to promote cell proliferation and self-renewal of APSCs.
Keywords: forkhead box family C1 (FOXC1), stress-inducible protein 1 (STI-1), arachnoid-pia stem cells (APSCs)