Klein Luise, Ophelders Daan R M G, van den Hove Daniel, Damoiseaux Maurits, Rutten Bart P F, Reutelingsperger Chris P M, Schurgers Leon J, Wolfs Tim G A M
School for Oncology and Reproduction (GROW), Maastricht University, Maastricht, the Netherlands.
Department of Pediatrics, Maastricht University, Maastricht, the Netherlands.
Brain Behav Immun Health. 2022 May 2;23:100458. doi: 10.1016/j.bbih.2022.100458. eCollection 2022 Aug.
Systemic and cerebral inflammation following antenatal infection (e.g. chorioamnionitis) and dysregulation of the blood brain barrier (BBB) are major risk factors for abnormal neonatal brain development. Administration of multipotent adult progenitor cells (MAPCs) represents an interesting pharmacological strategy as modulator of the peripheral and cerebral immune response and protector of BBB integrity. We studied the immunomodulatory and protective cerebrovascular potential of prenatally administered MAPCs in a preclinical ovine model for antenatal inflammation. Ovine fetuses were intra-amniotically (i.a.) exposed to lipopolysaccharide (LPS) or saline at gestational day 125, followed by the intravenous administration of 1*10 MAPCs or saline at gestational day 127. Circulating inflammation markers were measured. Fetal brains were examined immuno-histochemically post-mortem at gestational day 132. Fetal plasma IL-6 levels were elevated significantly 24 h after LPS administration. systemic MAPC treatment after LPS exposure increased Annexin A1 (ANXA1) expression in the cerebrovascular endothelium, indicating enforcement of BBB integrity, and increased the number of leukocytes at brain barriers throughout the brain. Further characterisation of brain barrier-associated leukocytes showed that monocyte/choroid plexus macrophage (IBA-1/CD206) and neutrophil (MPO) populations predominantly contributed to the LPS-MAPC-induced increase of CD45cells. In the choroid plexus, the percentage of leukocytes expressing the proresolving mediator ANXA1 tended to be decreased after LPS-induced antenatal inflammation, an effect reversed by systemic MAPC treatment. Accordingly, expression levels of ANXA1 per leukocyte were decreased after LPS and restored after subsequent MAPC treatment. Increased expression of ANXA1 by the cerebrovasculature and immune cells at brain barriers following MAPC treatment in an infectious setting indicate a MAPC driven early defence mechanism to protect the neonatal brain against infection-driven inflammation and potential additional pro-inflammatory insults in the neonatal period.
产前感染（如绒毛膜羊膜炎）后的全身和脑部炎症以及血脑屏障（BBB）失调是新生儿脑发育异常的主要危险因素。给予多能成人祖细胞（MAPCs）是一种有趣的药理学策略，可作为外周和脑部免疫反应的调节剂以及BBB完整性的保护剂。我们在产前炎症的临床前绵羊模型中研究了产前给予MAPCs的免疫调节和脑血管保护潜力。在妊娠第125天，将绵羊胎儿羊膜腔内（i.a.）暴露于脂多糖（LPS）或生理盐水，随后在妊娠第127天静脉注射1×10 MAPCs或生理盐水。测量循环炎症标志物。在妊娠第132天对胎儿大脑进行死后免疫组织化学检查。LPS给药后24小时，胎儿血浆IL-6水平显著升高。LPS暴露后全身MAPC治疗增加了脑血管内皮细胞中膜联蛋白A1（ANXA1）的表达，表明BBB完整性增强，并增加了整个大脑脑屏障处的白细胞数量。对脑屏障相关白细胞的进一步表征表明，单核细胞/脉络丛巨噬细胞（IBA-1/CD206）和中性粒细胞（MPO）群体主要促成了LPS-MAPC诱导的CD45细胞增加。在脉络丛中，LPS诱导的产前炎症后，表达促消退介质ANXA1的白细胞百分比趋于降低，全身MAPC治疗可逆转这一效应。因此，LPS后每个白细胞的ANXA1表达水平降低，随后MAPC治疗后恢复。在感染环境中，MAPC治疗后脑血管和脑屏障处免疫细胞中ANXA1表达增加，表明MAPC驱动的早期防御机制可保护新生儿脑免受感染驱动的炎症以及新生儿期潜在的额外促炎损伤。
