Establishment of bone marrow-derived M-CSF receptor-dependent self-renewing macrophages
Establishment of bone marrow-derived M-CSF receptor-dependent self-renewing macrophages
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DOI：
10.1038/s41420-020-00300-3
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发表时间：
2020-07-23
影响因子：
7
通讯作者：
Suzu, Shinya
中科院分区：
文献类型：
--
作者：
Nasser, Hesham;Adhikary, Partho;Suzu, Shinya
最近的研究表明，组织巨噬细胞除来源于骨髓单核细胞外，还来源于卵黄囊前体细胞或胎肝单核细胞。这些细胞对组织巨噬细胞池的相对贡献尚不完全清楚，但胚胎来源的细胞被认为更重要，因为它们具有自我更新的能力。在这里，我们展示了成人骨髓来源的巨噬细胞的存在，它们保持着自我更新的能力。巨噬细胞集落刺激因子(M-CSF)是巨噬细胞发育的关键细胞因子，小鼠骨髓细胞经长期培养可获得具有自我更新功能的巨噬细胞。它们不会致瘤，在M-CSF存在下无限增殖。尽管与非增殖性巨噬细胞有一些不同，但它们保留了单核细胞系细胞的许多特征，包括分化为树突状细胞或破骨细胞。在参与胚胎干细胞自我更新的转录因子中，Kruppel样因子2(KLF2)在自我更新的巨噬细胞中被M-CSF强烈上调，同时伴随着抑制KLF2表达的转录因子MafB的下调。事实上，KLF2基因敲除导致了细胞周期停滞，并抑制了自我更新的巨噬细胞的细胞增殖。我们的新细胞模型将有助于揭示不同来源的自我更新巨噬细胞在表型、功能和增殖分子机制上的差异。
Recent studies have revealed that tissue macrophages are derived from yolk sac precursors or fetal liver monocytes, in addition to bone marrow monocytes. The relative contribution of these cells to the tissue macrophage pool is not fully understood, but embryo-derived cells are supposed to be more important because of their capacity to self-renew. Here, we show the presence of adult bone marrow-derived macrophages that retain self-renewing capacity. The self-renewing macrophages were readily obtained by long-term culture of mouse bone marrow cells with macrophage colony-stimulating factor (M-CSF), a key cytokine for macrophage development. They were non-tumorigenic and proliferated in the presence of M-CSF in unlimited numbers. Despite several differences from non-proliferating macrophages, they retained many features of cells of the monocytic lineage, including the differentiation into dendritic cells or osteoclasts. Among the transcription factors involved in the self-renewal of embryonic stem cells, Kruppel-like factor 2 (KLF2) was strongly upregulated upon M-CSF stimulation in the self-renewing macrophages, which was accompanied by the downregulation of MafB, a transcription factor that suppresses KLF2 expression. Indeed, knockdown of KLF2 led to cell cycle arrest and diminished cell proliferation in the self-renewing macrophages. Our new cell model would be useful to unravel differences in phenotype, function, and molecular mechanism of proliferation among self-renewing macrophages with different origins.