Nasser Hesham, Adhikary Partho, Abdel-Daim Amira, Noyori Osamu, Panaampon Jutatip, Kariya Ryusho, Okada Seiji, Ma Wenjuan, Baba Masaya, Takizawa Hitoshi, Yamane Mariko, Niwa Hitoshi, Suzu Shinya
Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811 Japan.
International Research Center for Medical Sciences, Kumamoto University, Kumamoto, 860-0811 Japan.
Cell Death Discov. 2020 Jul 23;6:63. doi: 10.1038/s41420-020-00300-3. eCollection 2020.
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, Krüppel-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.
最近的研究表明，除了骨髓单核细胞外，组织巨噬细胞还来源于卵黄囊前体或胎儿肝脏单核细胞。这些细胞对组织巨噬细胞库的相对贡献尚未完全了解，但胚胎来源的细胞因其自我更新能力而被认为更为重要。在此，我们展示了具有自我更新能力的成年骨髓来源巨噬细胞的存在。通过用巨噬细胞集落刺激因子（M-CSF，巨噬细胞发育的关键细胞因子）对小鼠骨髓细胞进行长期培养，很容易获得自我更新的巨噬细胞。它们不具有致瘤性，并且在M-CSF存在的情况下可无限增殖。尽管与非增殖性巨噬细胞存在一些差异，但它们保留了单核细胞谱系细胞的许多特征，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，Krüppel样因子2（KLF2）在自我更新的巨噬细胞受到M-CSF刺激后强烈上调，同时伴随着抑制KLF2表达的转录因子MafB的下调。事实上，敲低KLF2会导致自我更新的巨噬细胞细胞周期停滞并减少细胞增殖。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。
