AUTHOR=Li Xiaobo , Huang Qijing , Zhang Xiangxiang , Xie Changfeng , Liu Muyun , Yuan Yueming , Feng Jianjia , Xing Haoyu , Ru Li , Yuan Zheng , Xu Zhiyong , Yang YaoXiang , Long Yan , Xing Chengfeng , Song Jianping , Hu Xiang , Xu Qin 

TITLE=Reproductive and Developmental Toxicity Assessment of Human Umbilical Cord Mesenchymal Stem Cells in Rats

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=10

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.883996

DOI=10.3389/fcell.2022.883996

ISSN=2296-634X

ABSTRACT=<p><bold>Objective:</bold> 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.</p><p><bold>Methods:</bold> In the fertility and early embryonic development study, hUC-MSCs were administered at dose levels of 0, 6.0 × 10<sup>6</sup>, 8.5 × 10<sup>6</sup>, and 1.2 × 10<sup>7</sup>/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 × 10<sup>6</sup>, 1.2 × 10<sup>7</sup>, and 2.4 × 10<sup>7</sup>/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.</p><p><bold>Results:</bold> 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 × 10<sup>7</sup>/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 × 10<sup>7</sup>/kg, which could be due to pulmonary embolism.</p><p><bold>Conclusion:</bold> Based on the results of the studies, the no-observed-adverse-effect levels (NOAELs) are 8.5 × 10<sup>6</sup>/kg for fertility and early embryonic development, 1.2 × 10<sup>7</sup>/kg for maternal toxicity and 2.4 × 10<sup>7</sup>/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.</p>