PUA and C/EBPα/β convert fibroblasts into macrophage-like cells
PUA and C/EBPα/β convert fibroblasts into macrophage-like cells
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DOI：
10.1073/pnas.0711961105
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发表时间：
2008-04-22
影响因子：
11.1
通讯作者：
Graf, Thomas
中科院分区：
文献类型：
--
作者：
Feng, Ru;Desbordes, Sabrina C.;Graf, Thomas
早期的研究表明，转录因子C/EBP α诱导定向淋巴前体转分化为巨噬细胞，这一过程需要内源性PU.1。在这里，我们已经检查了PU.1和C/EBP α对成纤维细胞的影响，成纤维细胞是一种与血细胞关系较远的细胞类型，类似于成肌细胞、脂肪细胞、成骨细胞和成软骨细胞。这两种因子以及普阿和C/EBP β的组合诱导了大部分NIH 3 T3细胞中巨噬细胞/造血细胞表面标志物的上调。他们还在小鼠胚胎和成人皮肤来源的成纤维细胞中上调了这些标志物。基于细胞形态、巨噬细胞相关基因的激活和成纤维细胞相关基因的消失，含有减毒形式的PU.1和C/EBP α的细胞系获得了巨噬细胞样表型。这些细胞系还显示出巨噬细胞的功能：它们吞噬小颗粒和细菌，产生部分炎症反应，并表现出严格的CSF-1生长依赖性。髓系转化主要由普阿诱导，C/EBP α作为巨噬细胞特异性基因表达的调节剂。我们的数据表明，诱导皮肤来源的成纤维细胞转分化为组织再生所需的细胞类型是可能的。
Earlier work has shown that the transcription factor C/EBP alpha induced a transdifferentiation of committed lymphoid precursors into macrophages in a process requiring endogenous PU.1. Here we have examined the effects of PU.1 and C/EBP alpha on fibroblasts, a cell type distantly related to blood cells and akin to myoblasts, adipocytes, osteoblasts, and chondroblasts. The combination of the two factors, as well as PUA and C/EBP beta, induced the upregulation of macrophage/hematopoietic cell surface markers in a large proportion of NIH 3T3 cells. They also up-regulated these markers in mouse embryo- and adult skin-derived fibroblasts. Based on cell morphology, activation of macrophage-associated genes, and extinction of fibroblast-associated genes, cell lines containing an attenuated form of PU.1 and C/EBP alpha acquired a macrophage-like phenotype. The lines also display macrophage functions: They phagocytose small particles and bacteria, mount a partial inflammatory response, and exhibit strict CSF-1 dependence for growth. The myeloid conversion is primarily induced by PUA, with C/EBP alpha acting as a modulator of macrophage-specific gene expression. Our data suggest that it might become possible to induce the transdifferentiation of skin-derived fibroblasts into cell types desirable for tissue regeneration.