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

Abstract

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.

Repeat-dose toxicity study of human umbilical cord mesenchymal stem cells in cynomolgus monkeys by intravenous and subcutaneous injection

“…This is consistent with the alleviation of pulmonary embolism achieved by vascular expansion in the above reference. The symptoms of coma, decreased respiration, dilated pupils, decreased activity, and mental exhaustion in monkeys after repeated doses of hUC-MSCs (on the 3rd/4th dose prior to dilution of the concentration) may be typical of those associated with pulmonary embolism, consistent with many reports in the literature (Jung et al, 2013;Tatsumi, Ohashi, Matsubara et al, 2013;Li et al, 2022). However, it is also necessary to exclude whether this is due to an allergic reaction.…”

“…Frontiers in Cell and Developmental Biology frontiersin.org experiments and clinical trials (Lee, Seo, Pulin et al, 2009;Jung, Kwon, Choi et al, 2013;Liu, Chiang, Hung et al, 2017;Li, Huang, Zhang et al, 2022). When MSCs were infused into the systemic circulation rapidly, most of the MSCs were immediately entrapped in the lung.…”

Umbilical cord mesenchymal stromal cells in serum-free defined medium display an improved safety profile

“…The evaluation of the safety of UCMSCs, including assessment of toxicity, abnormal immunological reactions, biodistribution, and tumorigenicity, is a major focus in the development of “cell-based therapies” [ 23 ]. UCMSCs cultured in FBS or platelet lysates have been increasingly shown to be safe without deterioration [ 24 – 26 ]. However, the usage of FBS or platelet lysates makes standardization of cell manufacturing process difficult because of the poorly defined nature.…”

Research on stem cell therapy for spinal cord injury: a bibliometric and visual analysis from 2018–2023

“…In the last 2 decades, the development of stem cells and regenerative medicine, as well as in-depth research on the pathophysiology of SCI, has provided new hope for its treatment ( Fan et al, 2022 ; Zhang et al, 2022 ). Stem cells can proliferate and self-renew under certain conditions and can further differentiate into multiple functional cells ( Ramotowski et al, 2019 ; Veneruso et al, 2019 ; Li et al, 2022 ). This new research direction has attracted the interest of many researchers, and a large amount of related literature has emerged.…”