Labuz Daniel F, Whitlock Ashlyn E, Kycia Ina, Zurakowski David, Fauza Dario O
Department of Surgery, Boston Children's Hospital/ Harvard Medical School, Boston, MA, United States.
Department of Surgery, Boston Children's Hospital/ Harvard Medical School, Boston, MA, United States.
J Pediatr Surg. 2023 Jan;58(1):8-13. doi: 10.1016/j.jpedsurg.2022.09.022. Epub 2022 Sep 26.
Transamniotic stem cell therapy (TRASCET) with mesenchymal stem cells (MSCs) has been shown to impact pulmonary vascular development and remodeling in experimental congenital diaphragmatic hernia (CDH), with secondary structural cardiac effects. We sought to determine whether TRASCET has any functional impact on term fetal pulmonary hemodynamics in the nitrofen model.
Time-dated pregnant rat dams (n = 13) received nitrofen on gestational day 9 (E9) to induce fetal CDH. Fetuses (n = 155) were divided into three groups: untreated (n = 45), and two groups receiving volume-matched intra-amniotic injections on E17 of either saline (sham; n = 46), or a suspension of amniotic fluid-derived MSCs (afMSCs) (TRASCET; n = 64). Donor afMSCs were syngeneic, phenotyped by flow cytometry, and "primed" by exposure to interferon-gamma and interleukin-1beta prior to administration in vivo. At term (E21), fetuses underwent Doppler flow assessment at the mid-pulmonary artery and 4-chamber echocardiogram. Pulmonary vascular resistance was estimated by pulmonary artery acceleration time (PAAT), max velocity (MaxV) and velocity time integral (VTI). Cardiac function was assessed by global longitudinal strain (GLS) and ejection fraction (EF) using speckle analyses. Healthy fetuses (n = 11) served as additional controls. Statistical analysis was by the Mann-Whitney U test RESULTS: High resolution ultrasound data could be obtained from 8 to 13 fetuses per group. The PAAT and the PAAT normalized to cardiac cycle time were significantly improved by TRASCET compared to both untreated and sham-treated CDH (p = 0.004 to <0.001 in all pairwise comparisons). The flow profile sharpness (MaxV:VTI) was increased in untreated (p = 0.06) and sham (p = 0.01) groups but normalized by TRASCET (p<0.01). There was no difference in GLS between TRASCET and either the untreated or sham groups (p = 0.25 to p = 0.93).
Transamniotic stem cell therapy improves pulmonary vascular resistance in early term fetuses in the Nitrofen model of congenital diaphragmatic hernia. Further focus on the functional pulmonary hemodynamic impact of this therapy is justified.
N/A (animal and laboratory study).
间充质干细胞（MSC）经羊膜干细胞治疗（TRASCET）已被证明会影响实验性先天性膈疝（CDH）的肺血管发育和重塑，并产生继发性心脏结构影响。我们试图确定TRASCET对硝呋太尔模型足月胎儿肺血流动力学是否有任何功能影响。
按预产期计时的孕鼠（n = 13）在妊娠第9天（E9）接受硝呋太尔以诱导胎儿CDH。胎儿（n = 155）分为三组：未治疗组（n = 45），以及两组在E17接受等体积羊膜内注射的组，一组注射生理盐水（假手术组；n = 46），另一组注射羊水来源的间充质干细胞（afMSC）悬液（TRASCET组；n = 64）。供体afMSC是同基因的，通过流式细胞术进行表型分析，并在体内给药前通过暴露于干扰素-γ和白细胞介素-1β进行“预处理”。足月时（E21），对胎儿进行肺动脉中部的多普勒血流评估和四腔心超声心动图检查。通过肺动脉加速时间（PAAT）、最大速度（MaxV）和速度时间积分（VTI）估计肺血管阻力。使用斑点分析通过整体纵向应变（GLS）和射血分数（EF）评估心脏功能。健康胎儿（n = 11）作为额外对照。采用曼-惠特尼U检验进行统计分析。结果：每组可获得8至13例胎儿的高分辨率超声数据。与未治疗和假手术治疗的CDH相比，TRASCET组的PAAT以及标准化为心动周期时间的PAAT均有显著改善（所有两两比较中p = 0.004至<0.001）。未治疗组（p = 0.06）和假手术组（p = 0.01）的血流剖面锐度（MaxV:VTI）增加，但TRASCET组使其恢复正常（p<0.01）。TRASCET组与未治疗组或假手术组之间的GLS无差异（p = 0.25至p = 0.93）。
在先天性膈疝的硝呋太尔模型中，经羊膜干细胞治疗可改善足月早期胎儿的肺血管阻力。进一步关注该治疗对肺血流动力学的功能影响是合理的。
无（动物和实验室研究）。
