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

摘要 由氧化应激（OS）和炎症引起的胎盘功能障碍是主要的病理生理学 不良妊娠结局（APO;约占所有妊娠的11%）。风险诱导的OS和 炎症损害各种胎盘稳态功能，导致APO。大多数APO 导致指示性或自发性早产，因为分娩是降低胎儿风险的唯一选择， 产妇死亡率和发病率。目前，没有成功的干预措施可用于降低 APO缺乏预防APO的治疗策略，部分原因是缺乏准确预测APO的模型。 重现人类胎盘病理学和人类胎儿（胎盘）-母体（F-M）的子宫内环境 隔栏.胎盘在每个妊娠期都表现出不同的细胞结构， O2环境目前的模型（例如，外植体、2D和transwell培养物、胎盘灌注和动物） 有几个局限性，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学的理解， APO的病理学为了克服这些现有的局限性，我们将开发一种新的胎盘（胎儿）-蜕膜 （母体）接口（PMi）5腔器官芯片（PMi-OOC），旨在模拟PMi结构和功能 代表三个孕期的每一个，具有特定的O2环境。获得的新知识 将是阐明胎盘生物学/病理学的关键。通过三个目标，我们推进我们的 当前胎盘OOC，并检验OS和炎症相关胎盘病理学的假设 破坏PMi体内平衡导致APO 具体目标是： SA 1：在有或没有PM 1的情况下，设计所有三个孕期特异性“健康、生理状态”PM 1 - 00 C。 添加母体蜕膜免疫细胞。 SA 2：开发妊娠期特异性疾病状态模型，以研究OS和炎症的影响。这 将使用抗氧化剂N-乙酰-L-半胱氨酸或抗炎性白细胞介素-10对模型进行验证 以减轻OS或炎症的影响。 这项研究将开发妊娠期特异性胎盘OOC模型，可用于研究健康， 妊娠期疾病状态以及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.