Byline: Ruo-Xu. Liu, Jie. Ma, Ning. Guo, Shao-Jun. Liu
Microglia, as the resident immune cells in the central nervous system, play important roles in regulating neuronal processes, such as neural excitability, synaptic activity, and apoptotic cell clearance. Growth factors can activate multiple signaling pathways in central nervous system microglia and can regulate their immune effects, but whether growth factors can affect the morphological characteristics and ultrastructure of microglia has not been reported. After microinjecting 300 nL of a growth factor cocktail, including 10 [micro]g/mL epidermal growth factor, 10 [micro]g/mL basic fibroblast growth factor, 10 [micro]g/mL hepatocyte growth factor and 10 [micro]g/mL insulin-like growth factor into adult rat cortex, we found that the number of IBA1-positive microglia around the injection area increased significantly, indicating local activation of microglia. All CD68-positive labeling co-localized with IBA1 in microglia. Cell bodies and protrusions of CD68-positive cells were strongly attached to or were engulfing neurons. Characteristic huge phagosomes were observed in activated phagocytes by electron microscopy. The phagosomes generally included non-degraded neuronal protrusions and mitochondria, yet they contained no myelin membrane or remnants, which might indicate selective phagocytosis by the phagocytes. The remnant myelin sheath after phagocytosis still had regenerative ability and formed 'myelin-like' structures around phagocytes. These results show that microinjection of a growth factor cocktail into the cerebral cortex of rodents can locally activate microglia and induce selective phagocytosis of neural structures by phagocytes. The study was approved by the Institute of Laboratory Animal Science, Beijing Institute of Basic Medical Sciences (approval No. IACUC-AMMS-2014-501) on June 30, 2014.
Microglia are a type of glial cell located throughout the central nervous system. Microglia are derived from monocytes that originate from the yolk sac and spread throughout the central nervous system by invading the primitive brain tissue in early development. During prenatal development, microglia rapidly proliferate and ultimately become the resident immune cells in the brain (Alliot et al., 1999; Ginhoux and Prinz, 2015; Lenz and McCarthy, 2015; Wolf et al., 2017; Gomes-Leal, 2019) with a stable population throughout life (Ajami et al., 2007; Ginhoux and Prinz, 2015). In the postnatal brain of mammals, microglia transform into a highly ramified phenotype and constantly screen their environment (Wolf et al., 2017). They also play an active part in many basic processes in healthy brain physiology, including cell proliferation and synaptic connectivity (Lenz and McCarthy, 2015).
Microglia can be activated by any type of pathological event or change in brain homeostasis (Wolf et al., 2017). This activation process is highly diverse and depends on the context and type of stress or pathology, such as brain trauma, spinal cord injury or hypoxic/ischemic damage (Perez-Dominguez et al., 2019). Once stimulated, microglia rapidly undergo a morphological transformation and retract their highly ramified, branched processes to take on an amoeboid form (Lenz and McCarthy, 2015; Ransohoff and El Khoury, 2015). Some bioactive substances, including inflammatory cytokines, bioactive factors, lipopolysaccharides, and chemokines (Kreutzberg, 1996), also strongly influence the pathological outcome or immune response of microglia (Wolf et al., 2017). Accumulating evidence...