Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
Integrated Research Center for Fetal Medicine, Johns Hopkin University, Baltimore, Maryland, USA.
Am J Reprod Immunol. 2022 Dec;88(6):e13638. doi: 10.1111/aji.13638. Epub 2022 Nov 2.
Fetal neuroinflammation has been linked to preterm birth-related intraamniotic infection and inflammation; However, the contribution of fetal sex and maternal race/ethnicity is unknown. To determine if fetal sex and maternal race/ethnicity influence neuroinflammation, an organ-on-chip (OOC) model were established under normal or pathologic conditions utilizing amniotic fluid.
OOC is composed of two-cell culture chambers connected by Type IV collagen-coated microchannels. Human fetal astroglia (SVGp12) and microglia (HMC3) were co-cultured at an 80:20 ratio in the inner chamber. The outer chamber contained amniotic fluid (AF) from male and female fetuses of White Hispanic (WH) and African-American (AA) pregnant women with or without lipopolysaccharide (LPS-100 ng/ml) and incubated for 48 h. Glial migration (brightfield microscopy), activation (Immunocytochemistry), and cytokine production (Luminex assays) were quantified and compared (N = 4 for each category of sex and race/ethnicity).
In a pooled analysis, AF+LPS did not induce glial activation or inflammatory changes compared to AF alone. When stratified by sex, male AF+LPS promoted significant glial activation (high CD11b:p < 0.05; low Iba1:p < 0.01) compared to male AF without LPS; however, this was not associated with changes in pro-inflammatory cytokines. When stratified by race/ethnicity, AF+LPS induced glial activation in both groups, but a differential increase in pro-inflammatory cytokines was seen between WH and AA AF (WH-interleukin-1β: p < 0.05; AA-interleukin-8: p < 0.01).
This OOC model of fetal neuroinflammation has determined that race/ethnicity differences do exist for perinatal brain injury. The fetal sex of neonates was not a determining factor of susceptibility to intraamniotic inflammation leading to neuroinflammation.
胎儿神经炎症与早产相关的羊膜内感染和炎症有关；然而，胎儿性别和产妇种族/民族的贡献尚不清楚。为了确定胎儿性别和产妇种族/民族是否会影响神经炎症，我们利用羊水建立了正常或病理条件下的类器官（OOC）模型。
OOC 由两个细胞培养室组成，通过 IV 型胶原涂覆的微通道连接。将人胎儿星形胶质细胞（SVGp12）和小胶质细胞（HMC3）以 80:20 的比例在内腔中共培养。外腔中含有来自白人西班牙裔（WH）和非裔美国人（AA）孕妇的男性和女性胎儿的羊水（AF），并加入或不加入脂多糖（LPS-100ng/ml），孵育 48 小时。通过明场显微镜测量、比较（N=每个性别和种族/民族类别 4 个）胶质细胞迁移（glial migration）、激活（activation）和细胞因子产生（cytokine production）。
在一项汇总分析中，与单独的 AF 相比，AF+LPS 并未诱导胶质细胞激活或炎症变化。按性别分层时，与男性 AF 相比，男性 AF+LPS 显著促进了胶质细胞的激活（高 CD11b：p<0.05；低 Iba1：p<0.01）；然而，这与促炎细胞因子的变化无关。按种族/民族分层时，AF+LPS 诱导了两组的胶质细胞激活，但 WH 和 AA AF 之间的促炎细胞因子水平升高存在差异（WH-白细胞介素-1β：p<0.05；AA-白细胞介素-8：p<0.01）。
该胎儿神经炎症的 OOC 模型已确定，围产期脑损伤确实存在种族/民族差异。新生儿的胎儿性别并不是导致羊膜内炎症导致神经炎症易感性的决定因素。
