Differentiation of human circulating fibrocytes as mediated by transforming growth factor-β and peroxisome proliferator-activated receptor γ
Differentiation of human circulating fibrocytes as mediated by transforming growth factor-β and peroxisome proliferator-activated receptor γ
复制标题
DOI：
10.1074/jbc.m703597200
复制
发表时间：
2007-08-03
影响因子：
4.8
通讯作者：
Strieter, Robert M.
中科院分区：
文献类型：
--
作者：
Hong, Kurt M.;Belperio, John A.;Strieter, Robert M.
纤维细胞是外周血中成纤维细胞样祖细胞的独特群体，最近已显示其具有可塑性以沿沿着间充质谱系分化，包括定型为肌成纤维细胞和脂肪细胞。在这里，我们证明了转化生长因子（TGF）β 1通过激活Smad 2/3和SAPK/JNK MAPK途径驱动纤维细胞向肌成纤维细胞分化，这反过来又刺激α-平滑肌肌动蛋白表达。我们确定SAPK/JNK信号传导在正反馈回路中起作用以调节Smad 2/3核可用性和Smad 2/3依赖性转录。相反，纤维细胞向脂肪细胞的分化是由过氧化物酶体增殖物激活受体（PPAR）γ激动剂曲格列酮驱动的，其与细胞质脂质积累和aP 2的诱导相关。曲格列酮治疗也破坏了TGF β 1激活的SAPK/JNK信号传导，导致Smad 2/3反式激活活性和α-平滑肌肌动蛋白表达降低。有趣的是，TGF β 1被证明对纤维细胞分化为脂肪细胞具有相互抑制作用。通过激活SAPK/JNK信号传导，其通常在脂肪形成期间被抑制，破坏了PPAR γ依赖性反式激活活性和aP 2表达的诱导。总之，在局部微环境生态位的背景下，PPAR γ和TGF β 1激活的微妙平衡通过SAPK/JNK信号传导驱动脂肪细胞或肌成纤维细胞分化途径的选择。
Fibrocytes are a distinct population of fibroblast-like progenitor cells in peripheral blood that have recently been shown to possess plasticity to differentiate along mesenchymal lineages, including commitment to myofibroblast and adipocyte cells. Here, we demonstrated that transforming growth factor (TGF) beta 1 drives fibrocyte-to-myofibroblast differentiation through activating Smad2/3 and SAPK/JNK MAPK pathways, which in turn stimulates alpha-smooth muscle actin expression. We determined that SAPK/JNK signaling acts in a positive feedback loop to modulate Smad2/3 nuclear availability and Smad2/3-dependent transcription. Conversely, fibrocyte-to-adipocyte differentiation is driven by the peroxisome proliferator-activated receptor (PPAR) gamma agonist troglitazone, which is associated with cytoplasmic lipid accumulation and induction of aP2. Treatment with troglitazone also disrupted TGF beta 1-activated SAPK/JNK signaling, leading to decreased Smad2/3 transactivation activity and alpha-smooth muscle actin expression. Interestingly, TGF beta 1 was demonstrated to have reciprocal inhibition on fibrocyte differentiation to adipocytes. By activating SAPK/JNK signaling, which is normally suppressed during adipogenesis, PPAR gamma-dependent transactivation activity and induction of aP2 expression were disrupted. Taken together, within the context of the local microenvironmental niche, the delicate balance of PPAR gamma and TGF beta 1 activation drives the selection of an adipocyte or myofibroblast differentiation pathway through SAPK/JNK signaling.