Bastos Jonathan, O'Brien Carleigh, Vara-Pérez Mónica, Mampay Myrthe, van Olst Lynn, Barry-Carroll Liam, Kancheva Daliya, Leduc Sophia, Lievens Ayla Line, Ali Leen, Vlasov Vladislav, Meysman Laura, Shakeri Hadis, Roelandt Ria, Van Hove Hannah, De Vlaminck Karen, Scheyltjens Isabelle, Yaqoob Fazeela, Lombroso Sonia I, Breugelmans Maria, Faron Gilles, Gomez-Nicola Diego, Gate David, Bennett F Chris, Movahedi Kiavash
Brain and Systems Immunology Laboratory, Brussels Center for Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Immunity. 2025 May 13;58(5):1269-1288.e12. doi: 10.1016/j.immuni.2025.04.006. Epub 2025 Apr 30.
Microglia and border-associated macrophages (BAMs) are critical for brain health, and their dysfunction is associated to disease. Replacing brain macrophages holds substantial therapeutic promise but remains challenging. Here, we demonstrate that monocytes can efficiently replace all brain macrophages. Monocytes readily replaced embryonal BAMs upon their depletion and engrafted as monocyte-derived microglia (Mo-Microglia) upon more sustained niche availability. Mo-Microglia expanded comparably to their embryonic counterparts and showed similar longevity. However, monocytes were unable to replicate the distinct identity of embryonically derived BAMs and microglia. Using xenotransplantation, we found that human monocytes exhibited similar behavior, enabling identification of putative Mo-Microglia in Alzheimer's disease individuals. In mice and humans, monocyte ontogeny shaped their identity as brain macrophages. Importantly, mouse fetal liver monocytes exhibited a distinct epigenetic landscape and could develop a bona fide microglial identity. Our results illuminate brain macrophage development and highlight monocytes as an abundant progenitor source for brain macrophage replacement therapies.
小胶质细胞和边界相关巨噬细胞（BAMs）对大脑健康至关重要，它们的功能障碍与疾病相关。替换脑巨噬细胞具有巨大的治疗前景，但仍然具有挑战性。在这里，我们证明单核细胞可以有效地替代所有脑巨噬细胞。单核细胞在胚胎BAMs耗竭后很容易替代它们，并在更持续的生态位可利用性时植入成为单核细胞衍生的小胶质细胞（Mo-小胶质细胞）。Mo-小胶质细胞的扩增与它们的胚胎对应物相当，并且显示出相似的寿命。然而，单核细胞无法复制胚胎来源的BAMs和小胶质细胞的独特身份。通过异种移植，我们发现人类单核细胞表现出相似的行为，从而能够在阿尔茨海默病个体中鉴定出假定的Mo-小胶质细胞。在小鼠和人类中，单核细胞的个体发生塑造了它们作为脑巨噬细胞的身份。重要的是，小鼠胎儿肝脏单核细胞表现出独特的表观遗传景观，并能够发展出真正的小胶质细胞身份。我们的结果阐明了脑巨噬细胞的发育，并突出了单核细胞作为脑巨噬细胞替代疗法丰富祖细胞来源的作用。
