Abstract: Neuronal regeneration to replenish lost neurons after injury is critical for brain repair. Microglia, brain-resident macrophages that have the propensity to accumulate at the site of injury, can be a potential source for replenishing lost neurons through fate conversion into neurons, induced by forced expression of neuronal lineage-specific transcription factors. However, it has not been strictly demonstrated that microglia, rather than central nervous system-associated macrophages, such as meningeal macrophages, convert into neurons. Here, we show that NeuroD1-transduced microglia can be successfully converted into neurons in vitro using lineage-mapping strategies. We also found that a chemical cocktail treatment further promoted NeuroD1-induced microglia-to-neuron conversion. NeuroD1 with loss-of-function mutation, on the other hand, failed to induce the neuronal conversion. Our results indicate that microglia are indeed reprogrammed into neurons by NeuroD1 with neurogenic transcriptional activity

Abstract: Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of-hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis

Abstract: Among the myeloid cells in the central nervous system (CNS) microglia are the main representatives of the innate immune system. Microglial fulfil tasks beyond phagocytosing debris and host defense against invading microorganism. During brain development microglia guide for example neurons for proper CNS formation, in adulthood they maintain tissue homeostasis and in aging microglia may become pro-inflammatory and finally exhausted. Recently, several endogenous and exogenous factors were identified that essentially shape the microglial phenotype during both steady-state and pathological conditions. On the one hand, microglia receive inputs from CNS-endogenous sources for example, via crosstalk with other glial cells and neurons but on the other hand microglia are also highly modulated by external signals. Among them, host microbiota--the host's resident bacteria--are vital regulators of the CNS innate immune system. This review summarizes key extrinsic and intrinsic factors, with special focus on the host microbiota, that essentially influence microglia functions and states during development, homeostasis, and disease