ProNGF Is a Cell‐Type‐Specific Mitogen for Adult Hippocampal and for Induced Neural Stem Cells

The role of proNGF, the precursor of nerve growth factor (NGF), in the biology of adult neural stem cells (aNSCs) is still unclear. Here, we analyzed adult hippocampal neurogenesis in AD11 transgenic mice, in which the constitutive expression of anti‐NGF antibody leads to an imbalance of proNGF over mature NGF. We found increased proliferation of progenitors but a reduced neurogenesis in the AD11 dentate gyrus (DG)‐hippocampus (HP). Also in vitro, AD11 hippocampal neural stem cells (NSCs) proliferated more, but were unable to differentiate into morphologically mature neurons. By treating wild‐type hippocampal progenitors with the uncleavable form of proNGF (proNGF‐KR), we demonstrated that proNGF acts as mitogen on aNSCs at low concentration. The mitogenic effect of proNGF was specifically addressed to the radial glia‐like (RGL) stem cells through the induction of cyclin D1 expression. These cells express high levels of p75NTR, as demonstrated by immunofluorescence analyses performed ex vivo on RGL cells isolated from freshly dissociated HP‐DG or selected in vitro from NSCs by leukemia inhibitory factor. Clonogenic assay performed in the absence of mitogens showed that RGLs respond to proNGF‐KR by reactivating their proliferation and thus leading to neurospheres formation. The mitogenic effect of proNGF was further exploited in the expansion of mouse‐induced neural stem cells (iNSCs). Chronic exposure of iNSCs to proNGF‐KR increased their proliferation. Altogether, we demonstrated that proNGF acts as mitogen on hippocampal and iNSCs. Stem Cells2019;37:1223–1237 Possible mechanism of action of the precursor of nerve growth factor in the hippocampal neurogenic niche. The scheme represents the maturation from quiescent radial glia‐like stem cells to neuroblasts. p75NTRprotein level decreases during the maturation path. Precursor of nerve growth factor produced within the niche is partially cleaved to release mature nerve growth factor, whereas some precursor of nerve growth factor remains unprocessed. This portion of precursor of nerve growth factor switches the quiescent radial glia‐like stem cells to the active state by cyclin D1 induction. Mature nerve growth factor acts at the end of the maturation path by promoting neuroblast survival. Finally, in our hypothesis, precursor of nerve growth factor drives programmed cell death in neuroblasts, so the incessant regulation of precursor of nerve growth factor cleavage is determinant for a balanced neurogenesis.