Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-04-24 DOI:10.1016/j.celrep.2025.115609

Jung-Seok Kim, Sébastien Trzebanski, Sun-Hye Shin, Lior Schori, Gal Ronit Frumer Friedman, Noa Chapal Ilani, Aditee Kadam, Rocio Vicario, Oliver Aust, Polina Bugaeva, Sylwia Piatek, Laura Kate Ismajli, Christian Johannes Hoffmann, Marina Scheller, Sigalit Boura-Halfon, Nathali Kaushansky, Ofra Golani, Aryeh Solomon, Zhaoyuan Liu, Lukas Amann, Philipp Böhm-Sturm, Stefan Paul Koch, Nikolaus Wenger, Florent Ginhoux, Marco Prinz, Roi Avraham, Christoph Harms, Frederic Geissmann, Carsten Müller-Tidow, Stefan Uderhardt, Ivan Milenkovic, Liran Shlush, Steffen Jung

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引用次数: 0

Abstract

Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment that resists seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles. Due to their hematopoietic stem cell (HSC) derivation, monocyte-derived microglia (MoMg) are unlike yolk-sac-derived cells, targets of clonal hematopoiesis (CH). Indeed, using a chimeric transfer model, we show that the hematopoietic expression of DNMT3A^R882H, a prominent human CH variant, renders MoMg pathogenic and promotes motor deficits resembling atypical Parkinsonian disorders. Collectively, we establish that MoMg progressively seed the brain of healthy aging mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can cause brain pathology.

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衰老小鼠单核细胞源性小胶质细胞积累引起的克隆造血相关运动障碍。

小胶质细胞是在胚胎发生过程中形成的脑实质巨噬细胞，形成一个自我包含的细胞室，抵抗来自成人最终造血的细胞的播种。我们报道单核细胞来源的巨噬细胞（MoMΦs）在具有不同拓扑结构的衰老小鼠的大脑中积累，包括黑纹状体和髓质，但不包括额叶皮层。实质MoMΦs采用真实小胶质细胞形态和表达谱。由于其造血干细胞（HSC）的衍生性，单核细胞衍生的小胶质细胞（MoMg）不同于克隆造血（CH）的靶点卵黄囊衍生细胞。事实上，使用嵌合转移模型，我们发现造血表达DNMT3AR882H（一种突出的人类CH变体）使MoMg具有致病性，并促进类似于非典型帕金森病的运动缺陷。总的来说，我们确定了MoMg逐渐在健康衰老小鼠的大脑中植入种子，在选定的区域积累，并且当携带与CH相关的体细胞突变时，可能导致大脑病理。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.