Reproductive and Developmental Toxicity Assessment of Human Umbilical Cord Mesenchymal Stem Cells in Rats.
Reproductive and Developmental Toxicity Assessment of Human Umbilical Cord Mesenchymal Stem Cells in Rats.
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DOI：
10.3389/fcell.2022.883996
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发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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目的：人脐带间充质干细胞（hUC-MSCs）在治疗多种疾病的临床应用中显示出非常诱人的潜力。然而，有关 hUC-MSC 的生殖和发育毒性的数据仍然不足。因此，我们评估了静脉注射 hUC-MSC 对 Sprague-Dawley 大鼠生殖和发育的潜在影响。 方法：在生育力和早期胚胎发育研究中，在交配前、交配和妊娠期对雄性和雌性大鼠按0、6.0×106、8.5×106和1.2×107/kg的剂量水平给予hUC-MSCs。在胚胎-胎儿发育研究中，怀孕雌性大鼠从妊娠第6-15天开始接受0、6.0×106、1.2×107和2.4×107/kg hUC-MSCs。评估内容包括死亡率、临床观察、体重、食物消耗、雄性和雌性生育力参数、窝产仔数和胎儿参数等。结果：未观察到hUC-MSCs对雄性和雌性大鼠生育力的相关毒性，对胎儿没有致畸作用。 1.2×107/kg hUC-MSCs导致雄性大鼠体重增加轻度下降，怀孕雌性大鼠出现短暂精神萎靡、呼吸急促和血尿症状。在2.4×107/kg剂量下观察到部分怀孕雌性死亡，可能是由于肺栓塞所致。 结论：根据研究结果，静脉注射hUC-MSCs的大鼠的生育力和早期胚胎发育的无观察不良反应水平（NOAEL）为8.5×106/kg，母体毒性为1.2×107/kg，胚胎-胎儿发育为2.4×107/kg，分别相当于其注射剂量的8.5倍、12倍和24倍。人体临床剂量。这些发现可能为hUC-MSCs的人类健康风险评估提供合理的依据。
Objective: Human umbilical cord mesenchymal stem cells (hUC-MSCs) have shown very attractive potential in clinical applications for the treatment of various diseases. However, the data about the reproductive and developmental toxicity of hUC-MSCs remains insufficient. Thus, we assessed the potential effects of intravenous injection of hUC-MSCs on reproduction and development in Sprague-Dawley rats. Methods: In the fertility and early embryonic development study, hUC-MSCs were administered at dose levels of 0, 6.0 × 106, 8.5 × 106, and 1.2 × 107/kg to male and female rats during the pre-mating, mating and gestation period. In the embryo-fetal development study, the pregnant female rats received 0, 6.0 × 106, 1.2 × 107, and 2.4 × 107/kg of hUC-MSCs from gestation days (GD) 6–15. Assessments made included mortality, clinical observations, body weight, food consumption, fertility parameters of male and female, litter, and fetus parameters, etc. Results: No hUC-MSCs-related toxicity was observed on the fertility of male and female rats, and no teratogenic effect on fetuses. hUC-MSCs at 1.2 × 107/kg caused a mildly decrease in body weight gain of male rats, transient listlessness, tachypnea, and hematuria symptoms in pregnant female rats. Death was observed in part of the pregnant females at a dose of 2.4 × 107/kg, which could be due to pulmonary embolism. Conclusion: Based on the results of the studies, the no-observed-adverse-effect levels (NOAELs) are 8.5 × 106/kg for fertility and early embryonic development, 1.2 × 107/kg for maternal toxicity and 2.4 × 107/kg for embryo-fetal development in rats intravenous injected with hUC-MSCs, which are equivalent to 8.5-fold, 12-fold, and 24-fold respectively of its clinical dosage in humans. These findings may provide a rational basis for human health risk assessment of hUC-MSCs.
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