Fc receptor engagement mediates differentiation of cardiac fibroblast precursor cells
Fc receptor engagement mediates differentiation of cardiac fibroblast precursor cells
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DOI：
10.1073/pnas.0804910105
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发表时间：
2008-07-22
影响因子：
11.1
通讯作者：
Entman, Mark L.
中科院分区：
文献类型：
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作者：
Haudek, Sandra B.;Trial, JoAnn;Entman, Mark L.
我们先前描述了成纤维细胞前体群体在小鼠纤维化心肌病模型（I/RC）发展中的关键作用。这些前体来源于单核细胞来源的循环骨髓源性细胞。血清淀粉样蛋白P（SAP）的管理，防止这种细胞群在心脏和心肌病的存在。由于SAP与单核细胞上表达的Fc受体（FcR）结合，我们研究了FcR信号转导的参与。我们选择了缺乏FcR γ链蛋白（FcR γ（-/-））的小鼠，FcR γ是激活FcR的常见膜信号成分。与野生型小鼠一样，FcR γ（-/-）小鼠在接受I/RC时发生纤维化和心功能障碍。然而，与野生型小鼠不同，FcR γ（-/-）小鼠中的SAP未能抑制纤维化和心功能障碍的发展，并且没有减少I/RC典型的α-平滑肌肌动蛋白（+）和CD 34（+）、CD 45（+）成纤维细胞的数量。为了进一步研究SAP在单核细胞向成纤维细胞转化中的作用，我们进行了体外试验，其中人外周血单核细胞（PBMC）通过人脐静脉内皮细胞（HUVEC）迁移。我们发现单核细胞的MCP-1依赖性跨内皮迁移显著加速了它们向成纤维细胞的分化。当在内皮细胞迁移之前将SAP加入PBMC悬浮液中时，这种单核细胞向成纤维细胞的分化被消除。在成功迁移后向细胞中加入SAP不会抑制成纤维细胞的成熟。这些数据表明，SAP通过在跨内皮迁移发生之前激活FcR来进行信号传导，从而抑制血液传播的骨髓细胞群分化为成纤维细胞。我们认为，FcR激活循环前体细胞可能代表一个新的治疗目标，不良重塑和心脏纤维化。
We previously described a critical role for a fibroblast precursor population in the development of a murine fibrotic cardiomyopathy model (I/RC). These precursors arose from circulating bone marrow-derived cells of monocytic origin. Administration of serum amyloid P (SAP) prevented the presence of this cell population in the heart and the cardiomyopathy. Because SAP binds to Fc receptors (FcRs) expressed on monocytes, we investigated the involvement of FcR signaling. We chose mice lacking the FcR gamma chain protein (FcR gamma(-/-)), a common membrane-signaling component of activating FcRs. Like wild-type mice, FcR gamma(-/-) mice developed fibrosis and cardiac dysfunction when subjected to I/RC. However, unlike wild-type mice, SAP in FcR gamma(-/-) mice failed to inhibit the development of fibrosis and cardiac dysfunction and did not diminish the numbers of a-smooth muscle actin(+) and CD34(+), CD45(+) fibroblasts that were typical for I/RC. To further examine the role of SAP in monocyte-to-fibroblast transition, we performed in vitro assays in which human peripheral blood mononuclear cells (PBMCs) migrated through human umbilical vein endothelial cells (HUVECs). We found that MCP-1-dependent transendothelial migration of monocytes markedly accelerated their differentiation into fibroblasts. This monocyte differentiation to fibroblasts was eliminated when SAP was added to the PBMC suspension before endothelial transmigration. Adding SAP to cells after successful migration did not inhibit fibroblast maturation. These data indicate that SAP inhibits the differentiation of a blood-borne, myeloid cell population into fibroblasts by signaling through activating FcRs before transendothelial migration has occurred. We suggest that FcR activation of circulating precursor cells may represent a new treatment target for adverse remodeling and cardiac fibrosis.