内皮-间质转化与心血管疾病的研究进展

内皮-间质转化(endothelial-to-mesenchymal transition,End MT)属于上皮-间质转化(epithelial-to-mesenchymal transition,EMT)的特殊类型,是内皮细胞在多种刺激因素作用下向间充质细胞转化的过程,在此过程中内皮细胞逐渐失去其形态和功能,获得增殖、迁移和合成胶原等间充质细胞表型特点.近来研究发现,内皮-间质转化在内皮功能调节,心肌、血管及瓣膜的发育和结构重塑等方面发挥着关键的作用,提示其在心血管疾病领域具有重要的研究意义.本文对内皮-间质转化的特点、功能、调节机制以及在心血管系统发育、心肌纤维化、肺动脉高压和动脉粥样硬化性血管重构等心血管疾病中的作用做一综述,以期为心血管疾病的防治提供新靶点.     

TNF-α induces endothelial–mesenchymal transition promoting stromal development of pancreatic adenocarcinoma

Endothelial–mesenchymal transition (EndMT) is an important source of cancer-associated fibroblasts (CAFs), which facilitates tumour progression. PDAC is characterised by abundant CAFs and tumour necrosis factor-α (TNF-α). Here, we show that TNF-α strongly induces human endothelial cells to undergo EndMT. Interestingly, TNF-α strongly downregulates the expression of the endothelial receptor TIE1, and reciprocally TIE1 overexpression partially prevents TNF-α-induced EndMT, suggesting that TNF-α acts, at least partially, through TIE1 regulation in this process. We also show that TNF-α-induced EndMT is reversible. Furthermore, TNF-α treatment of orthotopic mice resulted in an important increase in the stroma, including CAFs. Finally, secretome analysis identified TNFSF12, as a regulator that is also present in PDAC patients. With the aim of restoring normal angiogenesis and better access to drugs, our results support the development of therapies targeting CAFs or inducing the EndMT reversion process in PDAC.Subject terms: Cancer microenvironment, Cell signalling     

内皮细胞向间充质细胞的转分化

内皮细胞向间充质细胞转分化(endothelial-to-mesenchymal transition,EndMT)过程中,内皮从内皮层分离,获得间充质细胞表型,其特征是细胞连接能力下降,内皮标志物减少,获得间充质细胞标志物,并具有扩散和迁移特性。在受损组织中,内皮细胞能够通过EndMT转分化为成纤维细胞,因此具有EndMT特性的内皮细胞在组织重构和纤维化中发挥重要作用。EndMT不仅参与心脏发育这一重要过程也参与许多病理性疾病如癌症,心脏的纤维化和肺动脉高压等。所以,靶向EndMT对多种疾病具有潜在的治疗意义。     

EndMT: A promising and controversial field

The endothelial to mesenchymal transition (EndMT) is the process by which endothelial cells lose a portion of their cellular features and obtain certain characteristics of mesenchymal cells, including loss of tight junctions, increased motility, and increased secretion of extracellular matrix proteins. EndMT is involved in cardiac development and a variety of diseases processes, such as vascular or tissue fibrosis and tumor. However, its role in specific diseases remains under debate. This review summarizes EndMT-related diseases, existing controversies, different types of EndMT, and molecules and signaling pathways associated with the process.     

ALK2使内皮细胞转化为类干细胞的机制

内皮细胞向间充质细胞转分化（endothelial-to-mesenchymal transition,EndMT）过程是血管内皮细胞转化为类干细胞的基础,持续激活状态的ALK2在EndMT过程起到关键的促进作用,EndMT发生后内皮细胞能获得类干细胞的表现型.TGF-β2和BMP4作为特异性配体激活ALK2,下调某些内皮细胞标志物并上调某些间质细胞标志物,促进EndMT过程.此外,编码ALK2的基因序列在206号氨基酸上突变形成R206H ALK2后作用类似持续激活状态ALK2,同样也能达到促进内皮细胞向间充质细胞转分化的目的.     

Is cytochrome P450 3A4 regulated by menstrual cycle hormones in control endometrium and endometriosis?

The aim of this study is to investigate the effect of evodiamine on fibroblast activation in cardiac fibroblasts and endothelial to mesenchymal transition (EndMT) in human umbilical vein endothelial cells (HUVECs). Neonatal rat cardiac fibroblasts were stimulated with transforming growth factor beta 1 (TGF-β1) to induce fibroblast activation. After co-cultured with evodiamine (5, 10 μM), the proliferation and pro-fibrotic proteins expression of cardiac fibroblasts were evaluated. HUVECs were also stimulated with TGF-β1 to induce EndMT and treated with evodiamine (5, 10 μM) at the same time. The EndMT response in the HUVECs was evaluated as well as the capacity of the transitioned endothelial cells migrating to surrounding tissue. As a result, Evodiamine-blunted TGF-β1 induced activation of cardiac fibroblast into myofibroblast as assessed by the decreased expressions of α-SMA. Furthermore, evodiamine reduced the increased protein expression of fibrosis markers in neonatal and adult rat cardiac fibroblasts induced by TGF-β1. HUVECs stimulated with TGF-β1 exhibited lower expression levels of CD31, CD34, and higher levels of α-SMA, vimentin than the control cells. This phenotype was eliminated in the HUVECs treated with both 5 and 10 μM evodiamine. Evodiamine significantly reduced the increase in migration ability that occurred in response to TGF-β1 in HUVECs. In addition, the activation of Smad2, Smad3, ERK1/2, and Akt, and the nuclear translocation of Smad4 in both cardiac fibroblasts and HUVEC were blocked by evodiamine treatment. Thus, evodiamine could prevent cardiac fibroblasts from activation into myofibroblast and protect HUVEC against EndMT. These effects may be mediated by inhibition of the TGFβ pathway in both cardiac fibroblasts and HUVECs.     

Tie1 deficiency induces endothelial-mesenchymal transition

Endothelial-mesenchymal transition (EndMT) has a significant role in embryonic heart formation and in various pathologies. However, the molecular mechanisms that regulate EndMT induction remain to be elucidated. We show that suppression of receptor tyrosine kinase Tie1 but not Tie2 induces human endothelial cells to undergo EndMT and that Slug deficiency reverts this process. We find that Erk1/2, Erk5 and Akt cascades control Slug promoter activity induced by Tie1 deficiency. Interestingly, EndMT is present in human pancreatic tumour. We propose that EndMT associated with Tie1 downregulation participates in the pathological development of stroma observed in tumours.     

Autophagic secretion of HMGB1 from cancer-associated fibroblasts promotes metastatic potential of non-small cell lung cancer cells via NFκB signaling

Tumor progression requires the communication between tumor cells and tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are major components of stromal cells. CAFs contribute to metastasis process through direct or indirect interaction with tumor cells; however, the underlying mechanism is largely unknown. Here, we reported that autophagy was upregulated in lung cancer-associated CAFs compared to normal fibroblasts (NFs), and autophagy was responsible for the promoting effect of CAFs on non-small cell lung cancer (NSCLC) cell migration and invasion. Inhibition of CAFs autophagy attenuated their regulation on epithelial–mesenchymal transition (EMT) and metastasis-related genes of NSCLC cells. High mobility group box 1 (HMGB1) secreted by CAFs mediated CAFs’ effect on lung cancer cell invasion, demonstrated by using recombinant HMGB1, HMGB1 neutralizing antibody, and HMGB1 inhibitor glycyrrhizin (GA). Importantly, the autophagy blockade of CAFs revealed that HMGB1 release was dependent on autophagy. We also found HMGB1 was responsible, at least in part, for autophagy activation of CAFs, suggesting CAFs remain active through an autocrine HMGB1 loop. Further study demonstrated that HMGB1 facilitated lung cancer cell invasion by activating the NFκB pathway. In a mouse xenograft model, the autophagy specific inhibitor chloroquine abolished the stimulating effect of CAFs on tumor growth. These results elucidated an oncogenic function for secretory autophagy in lung cancer-associated CAFs that promotes metastasis potential, and suggested HMGB1 as a novel therapeutic target.Subject terms: Cancer microenvironment, Non-small-cell lung cancer, Metastasis, Translational research     

miR-222 inhibits cardiac fibrosis in diabetic mice heart via regulating Wnt/β-catenin-mediated endothelium to mesenchymal transition

miR-222 participates in many cardiovascular diseases, but its effect on cardiac remodeling induced by diabetes is unclear. This study evaluated the functional role of miR-222 in cardiac fibrosis in diabetic mice. Streptozotocin (STZ) was used to establish a type 1 diabetic mouse model. After 10 weeks of STZ injection, mice were intravenously injected with Ad-miR-222 to induce the overexpression of miR-222. miR-222 overexpression reduced cardiac fibrosis and improved cardiac function in diabetic mice. Mechanistically, miR-222 inhibited the endothelium to mesenchymal transition (EndMT) in diabetic mouse hearts. Mouse heart fibroblasts and endothelial cells were isolated and cultured with high glucose (HG). An miR-222 mimic did not affect HG-induced fibroblast activation and function but did suppress the HG-induced EndMT process. The antagonism of miR-222 by antagomir inhibited HG-induced EndMT. miR-222 regulated the promoter region of β-catenin, thus negatively regulating the Wnt/β-catenin pathway, which was confirmed by β-catenin siRNA. Taken together, our results indicated that miR-222 inhibited cardiac fibrosis in diabetic mice via negatively regulating Wnt/β-catenin-mediated EndMT.     

肿瘤相关成纤维细胞与肿瘤微环境

肿瘤的发展过程与肿瘤微环境密切相关,而肿瘤相关成纤维细胞(CAFs)是上述微环境中最主要的宿主细胞,CAFs是一类不同细胞源性的细胞群,可来源于多种细胞包括静止的成纤维细胞、上皮细胞、内皮细胞和间质干细胞的分化过程。体内和体外生物学实验均证实,成纤维细胞在肿瘤微环境中并不是被动的对肿瘤发展提供支持,而是发挥了至关重要的作用,所以靶向CAFs有望成为肿瘤治疗的新方向,对CAFs相关分子标记物和分子事件的进一步探索将为抗肿瘤的临床治疗提供新的思路。本文将对CAFs的来源以及CAFs对肿瘤发生发展、转移及VEGF耐受等方面的作用做一综述。     

Endothelial-to-mesenchymal transition contributes to cardiac fibrosis

Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-beta1 (TGF-beta1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.     

肿瘤相关成纤维细胞促进肿瘤侵袭转移的作用机制

肿瘤相关成纤维细胞(cancer-associated fibroblasts,CAFs)是肿瘤微环境中最主要的成分之一,在肿瘤的发生发展中发挥着必不可少的作用。骨髓和脂肪的局部组织固有成纤维细胞及间充质干细胞是CAFs来源的主要前体细胞。大量研究表明,CAFs并不作为单独细胞在肿瘤周围存在,而是和肿瘤细胞相互作用,促进肿瘤的生长与存活并维持其恶性倾向。肿瘤细胞可以影响CAFs前体的招募,并诱导正常成纤维细胞活化为CAFs;同时,CAFs可以分泌多种细胞因子、生长因子和细胞外基质蛋白质,促进肿瘤细胞的增殖、耐药及侵袭转移,从而影响肿瘤的预后。CAFs还参与血管淋巴管的生成、细胞外基质重塑、免疫抑制以及肿瘤细胞上皮间质转化等有利于肿瘤发生发展的外源性途径,为肿瘤细胞提供了一个良好的微环境。大量研究显示,研发靶向CAFs的药物可以中断其与肿瘤细胞之间的联系,从而抑制肿瘤的生长和转移。因此,深入了解CAFs促肿瘤的作用机制将有利于肿瘤治疗新靶点的发现。本文将对CAFs促进肿瘤侵袭转移的作用机制加以综述。