Leukemia Inhibitory Factor Is Required for Subventricular Zone Astrocyte Progenitor Proliferation and for Prokineticin-2 Production after a Closed Head Injury in Mice

Astrogliosis is one of the hallmarks of brain injury, and after a mild injury activated astrocytes subserve neuroprotective and pro-regenerative functions. We previously found that the astroglial response to closed head injury (CHI) was blunted in mice that were haplodeficient in leukemia inhibitory factor (LIF); therefore, the goal of these studies was to determine if the delayed astrogliosis was due to decreased recruitment of subventricular zone (SVZ) progenitors. CHI's were performed on post-natal day 20 on LIF heterozygous (Het) and wild-type (WT) mice. At 48 h post-CHI, astrocyte progenitor proliferation within the SVZ increased ∼250% in WT mice but was reduced by ∼200% in LIF Het mice compared with sham controls. Using neurospheres to model the SVZ, LIF increased the percentage of proliferating astrocyte progenitors by 2-fold compared with controls but had no effect on neural stem cell proliferation. To rule out the involvement of other cytokines, 105 cytokines were analyzed using a multi-plex array and with targeted validation on injured LIF Het versus WT neocortex. Of the cytokines analyzed, only prokineticin-2 (ProK2) required LIF signaling. Correspondingly, LIF-treated neurospheres expressed higher levels of ProK2, the ProK1 and ProK2 receptors (ProKR1 and ProKR2). Using in situ hybridization, ProK2 messenger RNA (mRNA) was most abundant in neocortical neurons and highly expressed within the SVZ. However, in contrast to LIF, ProK2 decreased astrocyte progenitor proliferation 2-fold. Altogether, these data demonstrate that LIF is necessary for astrocyte progenitor proliferation after injury and reveal a new role for LIF as an essential regulator of the neurotrophic factor ProK2.