Frondelli Michelle J, Levison Steven W
Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
Neurotrauma Rep. 2021 Jun 25;2(1):285-302. doi: 10.1089/neur.2020.0063. eCollection 2021.
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 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.
星形胶质细胞增生是脑损伤的标志性特征之一，轻度损伤后，活化的星形胶质细胞具有神经保护和促进再生的功能。我们之前发现，白血病抑制因子（LIF）单倍体不足的小鼠对闭合性颅脑损伤（CHI）的星形胶质细胞反应减弱；因此，这些研究的目的是确定延迟的星形胶质细胞增生是否是由于脑室下区（SVZ）祖细胞募集减少所致。在出生后第20天对LIF杂合子（Het）和野生型（WT）小鼠进行CHI。与假手术对照组相比，CHI后48小时，WT小鼠SVZ内星形胶质细胞祖细胞增殖增加约250%，而LIF Het小鼠则减少约200%。使用神经球模拟SVZ，与对照组相比，LIF使增殖的星形胶质细胞祖细胞百分比增加了2倍，但对神经干细胞增殖没有影响。为了排除其他细胞因子的参与，使用多重阵列分析了105种细胞因子，并对受伤的LIF Het与WT新皮质进行了靶向验证。在所分析的细胞因子中，只有促动力蛋白-2（ProK2）需要LIF信号传导。相应地，LIF处理的神经球表达更高水平的ProK2、ProK1和ProK2受体（ProKR1和ProKR2）。使用杂交技术，ProK2信使核糖核酸（mRNA）在新皮质神经元中最为丰富，并且在SVZ内高度表达。然而，与LIF相反，ProK2使星形胶质细胞祖细胞增殖减少了2倍。总之，这些数据表明LIF是损伤后星形胶质细胞祖细胞增殖所必需的，并揭示了LIF作为神经营养因子ProK2的重要调节因子的新作用。
