IGFBP2 promotes neural stem cell maintenance and proliferation differentially associated with glioblastoma subtypes

Abstract

Neural stem cells (NSCs) give rise to the central nervous system (CNS) and persist in certain areas of adult brains for replenishing damaged differentiated cells. The loss of the balance between NSC self-renewal and differentiation could lead to tumor formation such as the occurrence of glioblastoma (GBM), the most common and deadly human brain tumor, which could be derived from neural stem or stem-like cells. Early studies showed that insulin-like growth factor binding protein 2 (IGFBP2) mRNA levels were maintained high during the fetal brain development but decreased in the adult brains. We previously reported that IGFBP2 was frequently overexpressed in GBMs, which was correlated with GBM recurrence and poor survival and promoted glioma progression. However, the role of IGFBP2 in the CNS was not investigated yet, whose understanding will help elucidate IGFBP2 functions in GBM. In the study, we identify IGFBP2 as a critical molecule for mouse NSC maintenance. IGFBP2 is highly expressed in NSCs, and its expression exhibits an apical-basal pattern in the neural tube with a higher apical level and decreased with NSC differentiation during the CNS development. IGFBP2 promotes NSC self-renewal and proliferation but inhibits its differentiation to neurons and astrocytes. The knockdown of IGFBP2 significantly affected the expression of cell cycle, Notch pathway, and neural stemness and differentiation genes in NSCs. Further, the expression of IGFBP2-regulated cell cycle genes is significantly correlated with IGFBP2 expression in non-Mesenchymal GBM subtypes including Classical, Proneural, and Neural subtypes and of its Notch pathway genes differentially associated in the four GBM subtypes, altogether suggesting its critical and similar functions in NSCs and GBM cells.