Autocrine Regulation of Interferon γ in Mesenchymal Stem Cells Plays a Role in Early Osteoblastogenesis
Autocrine Regulation of Interferon γ in Mesenchymal Stem Cells Plays a Role in Early Osteoblastogenesis
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DOI：
10.1634/stemcells.2008-0886
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发表时间：
2009-01-01
期刊：
影响因子：
5.2
通讯作者：
Kremer, Richard
中科院分区：
文献类型：
--
作者：
Duque, Gustavo;Huang, Dao Chao;Kremer, Richard
干扰素（IFN）γ是破骨细胞分化和活性的强抑制剂。然而，其在成骨细胞发生中的作用尚未被仔细研究。利用微阵列表达分析，我们发现几个IFN γ诱导基因在人间充质干细胞（hMSCs）成骨分化的早期阶段上调。因此，我们假设IFN γ可能在这一过程中发挥作用。我们首先观察到hMSC诱导分化成成骨细胞后IFN γ产生的强烈和短暂的增加。接下来，我们使用小干扰RNA的敲低方法阻断了这种内源性产生，并观察到hMSC分化为成骨细胞的强烈抑制，同时Runx 2减少，Runx 2是成骨细胞发育不可或缺的因子。此外，外源性添加IFN γ以剂量依赖性方式加速hMSC向成骨细胞的分化，并在分化的早期阶段诱导更高水平的Runx 2表达。接下来，我们在IFN γ受体1敲除（IFN γ R1（-/-））小鼠中检查了体内IFN γ信号传导。与同窝野生型小鼠相比，IFN γ R1（-/-）小鼠的骨密度降低。如在体外实验中，从IFN γ R1（-/-）小鼠获得的MSC显示出较低的分化成骨细胞的能力。总之，我们证明，IFN γ的存在下起着重要的作用，在承诺的MSC成骨细胞系在体外和体内，这一过程可以加速外源性添加IFN γ。因此，这些数据支持IFN γ作为hMSC分化的自分泌调节剂和作为体内骨形成细胞的潜在新靶点的新作用。干细胞2009; 27：550-558
Interferon (IFN)gamma is a strong inhibitor of osteoclast differentiation and activity. However, its role in osteoblastogenesis has not been carefully examined. Using microarray expression analysis, we found that several IFN gamma-inducible genes were upregulated during early phases of osteoblast differentiation of human mesenchymal stem cells (hMSCs). We therefore hypothesized that IFN gamma may play a role in this process. We first observed a strong and transient increase in IFN gamma production following hMSC induction to differentiate into osteoblasts. We next blocked this endogenous production using a knockdown approach with small interfering RNA and observed a strong inhibition of hMSC differentiation into osteoblasts with a concomitant decrease in Runx2, a factor indispensable for osteoblast development. Additionally, exogenous addition of IFN gamma accelerated hMSC differentiation into osteoblasts in a dose-dependent manner and induced higher levels of Runx2 expression during the early phase of differentiation. We next examined IFN gamma signaling in vivo in IFN gamma receptor 1 knockout (IFN gamma R1(-/-)) mice. Compared with their wildtype littermates, IFN gamma R1(-/-) mice exhibited a reduction in bone mineral density. As in the in vitro experiments, MSCs obtained from IFN gamma R1(-/-) mice showed a lower capacity to differentiate into osteoblasts. In summary, we demonstrate that the presence of IFN gamma plays an important role during the commitment of MSCs into the osteoblastic lineage both in vitro and in vivo, and that this process can be accelerated by exogenous addition of IFN gamma. These data therefore support a new role for IFN gamma as an autocrine regulator of hMSC differentiation and as a potential new target of bone-forming cells in vivo. STEM CELLS 2009; 27: 550-558