Placental syncytium forms a biophysical barrier against pathogen invasion.
Placental syncytium forms a biophysical barrier against pathogen invasion.
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DOI：
10.1371/journal.ppat.1003821
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Bakardjiev AI
中科院分区：
文献类型：
--
作者：
Zeldovich VB;Clausen CH;Bradford E;Fletcher DA;Maltepe E;Robbins JR;Bakardjiev AI
胎儿合胞体滋养层形成一个独特的融合多核表面，沐浴在母体血液中，构成胎儿和母亲之间的主要界面。合体滋养层细胞暴露于母体血液中循环的病原体，并且似乎对微生物入侵具有独特的抵抗机制。这部分是由于缺乏细胞间连接及其受体，极化单核上皮细胞的致命弱点。然而，合胞体对受体非依赖性入侵也具有免疫力，这表明了针对感染的额外的一般防御机制。在培养中维持和操纵原代人合胞体滋养层细胞的困难使得研究这种独特组织中宿主防御的细胞和分子基础具有挑战性。在这里，我们提出了一个新的系统来研究胎盘的发病机制，使用鼠滋养层干细胞（mTSC），可以分化成合胞体滋养层细胞和重演人类胎盘合胞体。与先前在原代人体器官培养中的结果一致，发现鼠合胞体滋养层细胞通过直接侵入和细胞间传播对单核细胞增生李斯特菌感染具有抗性。原子力显微镜的小鼠合体滋养层细胞表明，这些细胞有一个更大的弹性模量比单核滋养层。用细胞松弛素D破坏异常致密的肌动蛋白结构（一种弥漫的微丝网络），导致其弹性模量降低25%。这与L.单核细胞增多症进入鼠和人合胞体。这些结果表明，合胞体肌动蛋白细胞骨架可能形成一个一般的障碍，对病原体进入人类和小鼠。此外，鼠TSC是用于研究合胞体宿主防御中的特定途径的遗传上易处理的模型系统。胎盘感染可导致妊娠并发症以及胎儿和母体疾病和死亡。我们开发了一种新的系统来研究胎盘感染，使用小鼠胎儿胎盘祖细胞和细菌病原体单核细胞增生李斯特菌。在成熟的胎盘中，胎儿祖细胞融合形成一个大的表面（合胞体），它沐浴在母体血液中，并介导母体和胎儿循环之间的营养和气体交换。我们发现合胞体抵抗物理变形，其不寻常的细胞骨架组织有助于其弹性。其弹性减弱与感染易感性增加有关。我们的研究提出了一种研究胎盘感染的新系统，并为胎盘屏障的性质提供了新的见解。
Fetal syncytiotrophoblasts form a unique fused multinuclear surface that is bathed in maternal blood, and constitutes the main interface between fetus and mother. Syncytiotrophoblasts are exposed to pathogens circulating in maternal blood, and appear to have unique resistance mechanisms against microbial invasion. These are due in part to the lack of intercellular junctions and their receptors, the Achilles heel of polarized mononuclear epithelia. However, the syncytium is immune to receptor-independent invasion as well, suggesting additional general defense mechanisms against infection. The difficulty of maintaining and manipulating primary human syncytiotrophoblasts in culture makes it challenging to investigate the cellular and molecular basis of host defenses in this unique tissue. Here we present a novel system to study placental pathogenesis using murine trophoblast stem cells (mTSC) that can be differentiated into syncytiotrophoblasts and recapitulate human placental syncytium. Consistent with previous results in primary human organ cultures, murine syncytiotrophoblasts were found to be resistant to infection with Listeria monocytogenes via direct invasion and cell-to-cell spread. Atomic force microscopy of murine syncytiotrophoblasts demonstrated that these cells have a greater elastic modulus than mononuclear trophoblasts. Disruption of the unusually dense actin structure – a diffuse meshwork of microfilaments - with Cytochalasin D led to a decrease in its elastic modulus by 25%. This correlated with a small but significant increase in invasion of L. monocytogenes into murine and human syncytium. These results suggest that the syncytial actin cytoskeleton may form a general barrier against pathogen entry in humans and mice. Moreover, murine TSCs are a genetically tractable model system for the investigation of specific pathways in syncytial host defenses. Infection of the placenta can lead to pregnancy complications as well as fetal and maternal disease and death. We developed a novel system to study placental infections using murine fetal placental progenitor cells and the bacterial pathogen Listeria monocytogenes. In the mature placenta fetal progenitor cells fuse to form a large surface (syncytium) that is bathed in maternal blood and mediates nutrient and gas exchange between maternal and fetal circulation. We found that the syncytium resists physical deformation, and that its unusual cytoskeletal organization contributes to its elasticity. Weakening of its elastic properties correlated with increased susceptibility to infection. Our study presents a novel system to study placental infections, and provides new insights into the nature of the placental barrier.
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DOI：
10.1083/jcb.201106011
发表时间：
2011-10-31
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bonazzi M;Cossart P
通讯作者：
Cossart P
影响因子：
3.7
作者：
Choi HJ;Sanders TA;Tormos KV;Ameri K;Tsai JD;Park AM;Gonzalez J;Rajah AM;Liu X;Quinonez DM;Rinaudo PF;Maltepe E
通讯作者：
Maltepe E
DOI：
10.1073/pnas.1304718110
发表时间：
2013-07-16
影响因子：
11.1
作者：
Delorme-Axford, Elizabeth;Donker, Rogier B.;Coyne, Carolyn B.
通讯作者：
Coyne, Carolyn B.
影响因子：
3.1
作者：
Bakardjiev, AI;Stacy, BA;Portnoy, DA
通讯作者：
Portnoy, DA
影响因子：
8.6
作者：
BEHM, RJ;HOSLER, W;BINNIG, G
通讯作者：
BINNIG, G