Kikhia Majed, Schilling Simone, Herzog Marie-Louise, Livne Michelle, Semtner Marcus, Tay Tuan Leng, Prinz Marco, Kettenmann Helmut, Endres Matthias, Kronenberg Golo, Göttert Ria, Gertz Karen
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neurology with Experimental Neurology, Charitéplatz 1, 10117, Berlin, Germany.
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Stroke Research Berlin (CSB), Charitéplatz 1, 10117, Berlin, Germany.
Nat Commun. 2025 Sep 16;16(1):8294. doi: 10.1038/s41467-025-63949-3.
Microglial proliferation is a principal element of the inflammatory response to brain ischemia. However, the precise proliferation dynamics, phenotype acquisition, and functional consequences of newly emerging microglia are not yet understood. Using multicolor fate mapping and computational methods, we here demonstrate that microglia exhibit polyclonal proliferation in the ischemic lesion of female mice. The peak number of clones occurs at 14 days, while the largest clones are observed at 4 weeks post-stroke. Whole-cell patch-clamp recordings of microglia reveal a homogeneous acute response to ischemia with a pattern of outward and inward currents that evolves over time. In the resolution phase, 8 weeks post-stroke, microglial cells within one clone share similar membrane properties, while neighboring microglia from different clones display more heterogeneous electrophysiological profiles. Super-resolution microscopy and live-cell imaging unmask various forms of cell-cell interactions between microglial cells from different clones. Overall, this study demonstrates the polyclonal proliferation of microglia after cerebral ischemia and suggests that clonality contributes to their functional heterogeneity. Thus, targeting clones with specific functional phenotypes may have potential for future therapeutic modulation of microglia after stroke.
小胶质细胞增殖是脑缺血炎症反应的主要因素。然而，新出现的小胶质细胞的精确增殖动态、表型获得及功能后果尚不清楚。我们利用多色命运图谱和计算方法证明，雌性小鼠缺血性病变中的小胶质细胞表现出多克隆增殖。克隆的峰值数量出现在14天，而最大的克隆在中风后4周观察到。对小胶质细胞进行全细胞膜片钳记录，发现其对缺血有一致的急性反应，伴有随时间变化的外向和内向电流模式。在中风后8周的消退期，一个克隆内的小胶质细胞具有相似的膜特性，而来自不同克隆的相邻小胶质细胞则表现出更多样化的电生理特征。超分辨率显微镜和活细胞成像揭示了不同克隆的小胶质细胞之间存在多种形式的细胞间相互作用。总体而言，本研究证明了脑缺血后小胶质细胞的多克隆增殖，并表明克隆性导致了它们的功能异质性。因此，针对具有特定功能表型的克隆可能对中风后小胶质细胞的未来治疗调控具有潜力。
