Hematopoietic stem cell transplantation chemotherapy causes microglia senescence and peripheral macrophage engraftment in the brain
Hematopoietic stem cell transplantation chemotherapy causes microglia senescence and peripheral macrophage engraftment in the brain
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DOI：
10.1038/s41591-022-01691-9
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发表时间：
2022-02-21
期刊：
影响因子：
82.9
通讯作者：
Cartier, Nathalie
中科院分区：
文献类型：
--
作者：
Sailor, Kurt A.;Agoranos, George;Cartier, Nathalie
造血干细胞移植（HSCT）是一种用于多种恶性和非恶性疾病的治疗方法，化疗用于移植前骨髓消融。造血干细胞移植后的大脑中含有外周移植的实质巨噬细胞，而正常大脑中没有，其移植机制尚不清楚。在这里，我们表明HSCT化疗广泛地破坏了小鼠的大脑再生群体，包括永久性地失去成年神经发生。小胶质细胞密度减半，导致小胶质细胞过程扩张，与广泛衰老的指标一致。虽然小胶质细胞表达细胞增殖标志物，但它们在S期细胞周期阻滞，大多数表达衰老和抗凋亡标志物p21。小胶质细胞从化学耗竭中恢复后的体内单细胞追踪显示其再生能力丧失，随后被供体巨噬细胞所取代。我们提出HSCT化疗导致小胶质细胞衰老，逐渐减少到临界小胶质细胞密度，为外周巨噬细胞植入大脑提供了一个允许的生态位。造血干细胞移植化疗布苏凡导致小鼠脑小胶质细胞衰老，成体神经发生迅速丧失，移植后外周供体巨噬细胞植入大脑。
Hematopoietic stem cell transplantation (HSCT) is a therapy used for multiple malignant and nonmalignant diseases, with chemotherapy used for pretransplantation myeloablation. The post-HSCT brain contains peripheral engrafted parenchymal macrophages, despite their absence in the normal brain, with the engraftment mechanism still undefined. Here we show that HSCT chemotherapy broadly disrupts mouse brain regenerative populations, including a permanent loss of adult neurogenesis. Microglial density was halved, causing microglial process expansion, coinciding with indicators of broad senescence. Although microglia expressed cell proliferation markers, they underwent cell cycle arrest in S phase with a majority expressing the senescence and antiapoptotic marker p21. In vivo single-cell tracking of microglia after recovery from chemical depletion showed loss of their regenerative capacity, subsequently replaced with donor macrophages. We propose that HSCT chemotherapy causes microglial senescence with a gradual decrease to a critical microglial density, providing a permissive niche for peripheral macrophage engraftment of the brain.Hematopoietic stem cell transplantation chemotherapy with busulfan causes senescence of brain microglia, rapid loss of adult neurogenesis and engraftment of peripheral donor macrophages into the brain of mice post transplantation.