iPS細胞由来ミクログリアを用いたニコチン性アセチルコリン受容体を標的とした機能制御の解析

抄録

Microglia are tissue-resident macrophages located in brain parenchyma and play key roles not only in brain immunity but also interact with neurons to contribute to neurogenesis, axonal growth, and synaptic refinement. The origin of microglia has been shown to be primitive macrophages that arise in the yolk sac during embryonic hematopoiesis colonize the developing brain prior to the establishment of the blood-brain-barrier. Alzheimer's disease (AD) is the progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ). Clearance by Aβ phagocytosis has been suggested as a function of microglia in AD brains. We here prepare the mouse induced pluripotent stem cells (iPSCs)-derived primitive macrophage (iMacs) as a cellular model of microglia that recapitulates their cellular origin and examined the functional regulation targeting on nicotinic acetylcholine receptors (nAChRs). We further examined cellular derivation into the brain by the peripheral injection of iMacs for the future cell therapeutic strategy for AD. Stimulation of α7 nAChR on iMacs by galantamine promoted Aβ phagocytosis. iMacs were further transplanted via tail vein after endogenous microglia depletion with PLX3397, an inhibitor of colony stimulating factor 1 receptor, and X-ray irradiation. As a result, a part of iMacs was found in the brain. Analysis of microglial function using a cell model that takes into account the cellular origin may contribute to the development of therapeutic strategies for AD.