Richardson Lauren S, Kim Sungjin, Han Arum, Menon Ramkumar
Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine & Perinatal Research, The University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-1062, USA.
Lab Chip. 2020 Nov 24;20(23):4486-4501. doi: 10.1039/d0lc00875c.
Maternal infection (i.e., ascending infection) and the resulting host inflammatory response are risk factors associated with spontaneous preterm birth (PTB), a major pregnancy complication. However, the path of infection and its propagation from the maternal side to the fetal side have been difficult to study due to the lack of appropriate in vitro models and limitations of animal models. A better understanding of the propagation kinetics of infectious agents and development of the host inflammatory response at the feto-maternal (amniochorion-decidua, respectively) interface (FMi) is critical in curtailing host inflammatory responses that can lead to PTB. To model ascending infection and determine inflammatory responses at the FMi, we developed a microfluidic organ-on-chip (OOC) device containing primary cells from the FMi (decidua, chorion, and amnion [mesenchyme and epithelium]) and collagen matrix harvested from primary tissue. The FMi-OOC is composed of four concentric circular cell/collagen chambers designed to mimic the thickness and cell density of the FMi in vivo. Each layer is connected by arrays of microchannels filled with type IV collagen to recreate the basement membrane of the amniochorion. Cellular characteristics (viability, morphology, production of nascent collagen, cellular transitions, and migration) in the OOC were similar to those seen in utero, validating the physiological relevance and utility of the developed FMi-OOC. The ascending infection model of the FMi-OOC, triggered by exposing the maternal (decidua) side of the OOC to lipopolysaccharide (LPS, 100 ng mL-1), shows that LPS propagated through the chorion, amnion mesenchyme, and reached the fetal amnion within 72 h. LPS induced time-dependent and cell-type-specific pro-inflammatory cytokine production (24 h decidua: IL-6, 48 h chorion: GM-CSF and IL-6, and 72 h amnion mesenchyme and epithelium: GM-CSF and IL-6). Collectively, this OOC model and study successfully modeled ascending infection, its propagation, and distinct inflammatory response at the FMi indicative of pathologic pathways of PTB. This OOC model provides a novel platform to study physiological and pathological cell status at the FMi, and is expected to have broad utility in the field of obstetrics.
母体感染（即上行感染）以及由此引发的宿主炎症反应是与自发性早产（PTB）相关的风险因素，PTB是一种主要的妊娠并发症。然而，由于缺乏合适的体外模型以及动物模型的局限性，感染途径及其从母体向胎儿传播的过程一直难以研究。更好地了解病原体的传播动力学以及胎儿-母体（分别为羊膜绒毛膜-蜕膜）界面（FMi）处宿主炎症反应的发展，对于抑制可能导致PTB的宿主炎症反应至关重要。为了模拟上行感染并确定FMi处的炎症反应，我们开发了一种微流控芯片器官（OOC）装置，该装置包含来自FMi的原代细胞（蜕膜、绒毛膜和羊膜[间充质和上皮]）以及从原代组织中获取的胶原基质。FMi-OOC由四个同心圆形细胞/胶原腔室组成，旨在模拟体内FMi的厚度和细胞密度。每一层通过填充有IV型胶原的微通道阵列相连，以重建羊膜绒毛膜的基底膜。OOC中的细胞特征（活力、形态、新生胶原的产生、细胞转变和迁移）与子宫内观察到的相似，验证了所开发的FMi-OOC的生理相关性和实用性。通过将OOC的母体（蜕膜）侧暴露于脂多糖（LPS，100 ng/mL）触发的FMi-OOC上行感染模型表明，LPS在72小时内通过绒毛膜、羊膜间充质传播并到达胎儿羊膜。LPS诱导了时间依赖性和细胞类型特异性的促炎细胞因子产生（24小时蜕膜：IL-6，48小时绒毛膜：GM-CSF和IL-6，72小时羊膜间充质和上皮：GM-CSF和IL-6）。总体而言，这个OOC模型和研究成功模拟了上行感染、其传播以及FMi处指示PTB病理途径的独特炎症反应。这个OOC模型为研究FMi处的生理和病理细胞状态提供了一个新平台，预计在产科领域具有广泛的应用。
