Neural stem/progenitor cells (NPC) have gained wide interest over the last decade from their therapeutic potential, either through
transplantation or endogenous replacement, after central nervous system (
CNS) disease and damage. Whereas several
growth factors and
cytokines have been shown to promote NPC survival, proliferation, or differentiation, the identification of other regulators will provide much needed options for NPC self-renewal or lineage development. Although previous studies have shown that
pituitary adenylate cyclase-activating polypeptide (
PACAP)/
vasoactive intestinal peptide (VIP) can regulate stem/progenitor cells, the responses appeared variable. To examine the direct roles of these
peptides in NPCs, postnatal mouse NPC cultures were withdrawn from
epidermal growth factor (
EGF) and fibroblastic
growth factor (FGF) and maintained under serum-free conditions in the presence or absence of
PACAP27,
PACAP38, or VIP. The NPCs expressed the PAC1(short)null receptor
isoform, and the activation of these receptors decreased progenitor cell apoptosis more than 80% from TUNEL assays and facilitated proliferation more than fivefold from
bromodeoxyuridine (
BrdU) analyses. To evaluate cellular differentiation, replicate control and
peptide-treated cultures were examined for cell fate marker
protein and transcript expression. In contrast with previous work,
PACAP peptides downregulated NPC differentiation, which appeared consistent with the proliferation status of the treated cells. Accordingly, these results demonstrate that
PACAP signaling is trophic and can maintain NPCs in a multipotent state. With these attributes,
PACAP may be able to promote endogenous NPC self-renewal in the adult CNS, which may be important for endogenous self-repair in disease and ageing processes.