Characteristics of pericardial interstitial cells and their implications in pericardial fibrocalcification.
Characteristics of pericardial interstitial cells and their implications in pericardial fibrocalcification.
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DOI：
10.1016/j.yjmcc.2012.09.008
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发表时间：
2012-12
影响因子：
5
通讯作者：
Xiaohong Liu;Meng-wei Tan;De-jun Gong;Lin Han;F. Lu;Sheng-dong Huang;Zhiyun Xu
中科院分区：
文献类型：
--
作者：
Xiaohong Liu;Meng-wei Tan;De-jun Gong;Lin Han;F. Lu;Sheng-dong Huang;Zhiyun Xu
心包纤维钙化（PF）是人类心包病理学的一个突出特征，包括缩窄性心包炎以及较小程度的退化自体心包替代物。然而，心包间质细胞（PIC）在 PF 发病机制中的作用尚未确定。结合组织学和免疫组织化学，我们发现原位 PF 的关键细胞事件是 PIC 转分化为肌成纤维细胞/成骨细胞，并且肌成纤维细胞/成骨细胞的百分比与 PF 的严重程度呈正相关。体外研究表明，PIC 与间充质干细胞类似，具有沿脂肪形成、成骨、软骨形成或肌源性谱系分化的潜力。然而，PIC表现出更有限的自我更新能力以及Oct4（POU5F1）和Kruppel样转录因子Klf4的较低表达，经历较早的衰老并自发转分化为肌成纤维细胞/成骨细胞。实时定量逆转录聚合酶链反应（qRT-PCR）证实α-平滑肌肌动蛋白（α-SMA）、碱性磷酸酶（ALP）、核心结合因子α1/runt相关转录因子2（Cbfa1/Runx2）、转化生长因子（TGF）-β1和骨形态发生蛋白的mRNA水平 (BMP)-2随着传代次数的增加而上调。血小板衍生生长因子 (PDGF)-AA 的 mRNA 水平也显着上调，在第 3 代时水平更高。Oct4 和 Klf4 的异位表达增强了 PIC 集落形成，并选择性损害参与转分化为肌成纤维细胞/成骨细胞的基因（α-SMA、ALP、Cbfa1/Runx2、 PDGF-AA 和 BMP-2)。这些数据在为 PIC 生物学提供新见解的同时，强化了这些细胞在细胞介导的 PF 中的核心作用，并可能有助于未来治疗纤维钙化心包疾病的策略。
Pericardial fibrocalcification (PF) is a prominent feature of human pericardial pathology, including constrictive pericarditis and, to a lesser extent, degenerated autologous pericardial substitutes. However, the role of pericardial interstitial cells (PICs) in the pathogenesis of PF has yet to be established. Using a combination of histology and immunohistochemistry, we showed that the critical cellular event in PF in situ was the transdifferentiation of PICs into myofibroblasts/osteoblasts and that the percentage of myofibroblasts/osteoblasts correlated positively with the severity of PF. In vitro studies demonstrated that PICs, similar to mesenchymal stem cells, had the potential to differentiate along adipogenic, osteogenic, chondrogenic or myogenic lineages. However, PICs exhibited a more limited self-renewal capacity and a lower expression of Oct4 (POU5F1) and Kruppel-like transcription factor Klf4, underwent earlier senescence and spontaneously transdifferentiated into myofibroblasts/osteoblasts. Quantitative-real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) confirmed that the mRNA levels of α-smooth muscle actin (α-SMA), alkaline phosphatase (ALP), core-binding factor α1/runt-related transcription factor2 (Cbfa1/Runx2), transforming growth factor (TGF)-β1 and bone morphogenetic protein (BMP)-2 were upregulated as the passage number increased. The mRNA level of platelet-derived growth factor (PDGF)-AA was also significantly upregulated with higher levels at passage 3. Ectopic expression of Oct4 and Klf4 enhanced the colony formation of PICs and selectively impaired induction of genes involved in transdifferentiation into myofibroblasts/osteoblasts (α-SMA, ALP, Cbfa1/Runx2, PDGF-AA and BMP-2). These data, while offering new insights into the biology of PICs, reinforce the central role of these cells in cell-mediated PF and may assist in future strategies to treat fibrocalcific pericardial diseases.