Lintao Ryan C V, Kammala Ananth Kumar, Radnaa Enkhtuya, Bettayeb Mohamed, Vincent Kathleen L, Patrikeev Igor, Yaklic Jerome, Bonney Elizabeth A, Menon Ramkumar
Division of Basic Science and Translational Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United States.
Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Manila, Philippines.
Front Cell Dev Biol. 2023 Sep 22;11:1256945. doi: 10.3389/fcell.2023.1256945. eCollection 2023.
During pregnancy, fetal cells can be incorporated into maternal tissues (fetal microchimerism), where they can persist postpartum. Whether these fetal cells are beneficial or detrimental to maternal health is unknown. This study aimed to characterize fetal microchimeric immune cells in the maternal heart during pregnancy and postpartum, and to identify differences in these fetal microchimeric subpopulations between normal and pregnancies complicated by spontaneous preterm induced by ascending infection. A Cre reporter mouse model, which when mated with wild-type C57BL/6J females resulted in cells and tissues of progeny expressing red fluorescent protein tandem dimer Tomato (mT+), was used to detect fetal microchimeric cells. On embryonic day (E)15, 10 colony-forming units (CFU) was administered intravaginally to mimic ascending infection, with delivery on or before E18.5 considered as preterm delivery. A subset of pregnant mice was sacrificed at E16 and postpartum day 28 to harvest maternal hearts. Heart tissues were processed for immunofluorescence microscopy and high-dimensional mass cytometry by time-of-flight (CyTOF) using an antibody panel of immune cell markers. Changes in cardiac physiologic parameters were measured up to 60 days postpartum via two-dimensional echocardiography. Intravaginal administration resulted in preterm delivery of live pups in 70% of the cases. mT + expressing cells were detected in maternal uterus and heart, implying that fetal cells can migrate to different maternal compartments. During ascending infection, more fetal antigen-presenting cells (APCs) and less fetal hematopoietic stem cells (HSCs) and fetal double-positive (DP) thymocytes were observed in maternal hearts at E16 compared to normal pregnancy. These HSCs were cleared while DP thymocytes persisted 28 days postpartum following an ascending infection. No significant changes in cardiac physiologic parameters were observed postpartum except a trend in lowering the ejection fraction rate in preterm delivered mothers. Both normal pregnancy and ascending infection revealed distinct compositions of fetal microchimeric immune cells within the maternal heart, which could potentially influence the maternal cardiac microenvironment via (1) modulation of cardiac reverse modeling processes by fetal stem cells, and (2) differential responses to recognition of fetal APCs by maternal T cells.
在孕期，胎儿细胞可整合至母体组织（胎儿微嵌合体），并在产后持续存在。这些胎儿细胞对母体健康是有益还是有害尚不清楚。本研究旨在表征孕期和产后母体心脏中的胎儿微嵌合免疫细胞，并确定正常妊娠与因上行感染导致的自发性早产妊娠之间这些胎儿微嵌合亚群的差异。使用一种Cre报告基因小鼠模型，当与野生型C57BL/6J雌性小鼠交配时，其后代的细胞和组织会表达红色荧光蛋白串联二聚体番茄红素（mT+），用于检测胎儿微嵌合细胞。在胚胎第15天（E15），经阴道给予10个集落形成单位（CFU）以模拟上行感染，在E18.5或之前分娩视为早产。一部分妊娠小鼠在E16和产后第28天处死，以获取母体心脏。心脏组织经处理后用于免疫荧光显微镜检查和使用免疫细胞标志物抗体组合的飞行时间高维质谱流式细胞术（CyTOF）。通过二维超声心动图测量产后60天内的心脏生理参数变化。经阴道给药导致70%的病例产下活的早产幼崽。在母体子宫和心脏中检测到表达mT+的细胞，这意味着胎儿细胞可迁移至不同的母体腔室。与正常妊娠相比，在E16时，上行感染期间母体心脏中观察到更多的胎儿抗原呈递细胞（APC），而胎儿造血干细胞（HSC）和胎儿双阳性（DP）胸腺细胞较少。这些造血干细胞在产后28天被清除，而上行感染后DP胸腺细胞持续存在。除了早产母亲的射血分数率有降低趋势外，产后未观察到心脏生理参数有显著变化。正常妊娠和上行感染均显示母体心脏内胎儿微嵌合免疫细胞的组成不同，这可能通过以下方式潜在地影响母体心脏微环境：（1）胎儿干细胞对心脏逆向建模过程的调节，以及（2）母体T细胞对胎儿APC识别的不同反应。
