Developing trimester-specific placenta organ-on-chips to model healthy and oxidative stress and inflammation-associated pathologies

摘要 氧化应激(OS)和炎症引起的胎盘功能障碍是主要的病理生理因素 不良妊娠结局的贡献者(APOS；约占所有妊娠的11%)。风险诱导型操作系统和 炎症损害了胎盘的各种稳态功能，导致APOS。大多数APO 导致指征或自然早产，因为分娩是降低胎儿宫缩风险的唯一选择。 产妇死亡率和发病率。目前，尚无成功的干预措施可用于降低 APOS。缺乏预防APOS的治疗策略的部分原因是缺乏准确的模型 重建人胎盘病理和人胎儿(胎盘)-母体(F-M)的宫内环境 障碍。胎盘在不同的孕期表现出不同的细胞密度 氧气环境。目前的模型(例如，外植体、2D和Transwell培养、胎盘灌流和动物) 有几个限制，因为它们没有解决胎盘和胎盘之间复杂和动态的相互作用 母体细胞，这阻碍了对正常妊娠期间胎盘生理的了解 APOS的病理改变。为了克服这些目前的局限性，我们将开发一种新的胎盘(胎儿)-蜕膜 (母体)接口(PMI)5腔片上器官(PMI-OOC)，旨在模拟PMI的结构和功能 代表三个怀孕三个月的每一个，具有特定的氧气环境。学到的新知识 这项研究将对阐明胎盘生物学/病理学至关重要。用三个目标，我们推进我们的 目前的胎盘OOC和检验OS和炎症相关胎盘病理的假说 影响PMI动态平衡，导致APOS。 具体目标是： SA 1：设计所有三个特定于三个月的“健康、生理状态”PMI-OOC，有或没有 增加母体蜕膜免疫细胞。 SA2：建立特定于三个月的疾病状态模型，以研究OS和炎症的影响。这 模型将通过使用抗氧化剂N-乙酰-L-半胱氨酸或抗炎白介素10进行验证 以减轻OS或炎症的影响。 这项研究将开发专门针对三个月的胎盘OOC模型，可用于研究健康、 此外，该中心还负责监测妊娠的疾病状态，并进行各种临床前试验。

ABSTRACT Placental dysfunctions arising from oxidative stress (OS) and inflammation are major pathophysiological contributors to adverse pregnancy outcomes (APOs; ~11% of all pregnancies). Risk-induced OS and inflammation compromise various placental homeostatic functions, leading to APOs. The majority of APOs lead to either indicated or spontaneous preterm birth, as delivery is the only option to reduce the risk of feto- maternal mortalities and morbidities. Currently, no successful interventions are available for reducing the risk of APOs. The lack of therapeutic strategies preventing APOs is partly due to the lack of models that accurately recreate human placenta pathology and the in utero environment of the human fetal (placental)-maternal (F-M) barriers. The placenta exhibits distinct cellularity in each of the pregnancy trimesters, which are under different O2 environments. Current models (e.g., explant, 2D and transwell cultures, placental perfusion, and animals) have several limitations as they do not address the complex and dynamic interplay between placental and maternal cells, which has hindered understanding of placental physiology during normal pregnancies and pathologies in APOs. To overcome these current limitations, we will develop a novel Placental (fetal)-decidual (Maternal) interface (PMi) 5-chamber organ-on-chip (PMi-OOC) designed to mimic PMi structure and function representing each of the three pregnancy trimesters, with specific O2 environments. New knowledge gained from this study will be crucial in elucidating placental biology/pathology. Using three aims, we advance our current placenta OOC and test the hypothesis that OS and inflammation-associated placental pathologies compromise PMi homeostasis, leading to APOs. Specific Aims are: SA 1: Engineer all three trimester-specific “healthy, physiological state” PMi-OOCs with or without the addition of maternal decidua immune cells. SA2: Develop a trimester-specific disease state model to study the effects of OS and inflammation. This model will be validated with the use of antioxidant N-Acetyl-L-Cysteine or anti-inflammatory interleukin-10 to mitigate the effect of OS or inflammation. This research will develop trimester-specific placenta OOC models that can be utilized to study healthy, and disease states of pregnancy as well as conduct various preclinical trials.