Bio-distribution and Toxicity Potential of Human Umbilical Cord Mesenchymal Stem Cells in Cynomolgus Monkeys

Abstract Mesenchymal stem cells (MSCs) have demonstrated promising advantages in the therapies of many diseases, while its multi-directional differentiation potential and immunotoxicity are the major concerns hindered their clinical translation. In this study, human umbilical Mesenchymal stem cell (hUC-MSCs) were labeled with a near-infrared fluorescent dye DiR before infused into Cynomolgus monkeys, and the amount of hUC-MSCs in the peripheral blood were dynamically estimated from 5 min to 28 days post a single administration at 3 × 10⁶ cells/kg and 2 × 10⁷ cells/kg intravenously. As results, some hUC-MSCs distributed to the whole body within 5 minutes, while most of the cells accumulate in the lungs along with the systemic blood circulation, and subsequently released into the blood. The toxicity potentials of hUC-MSCs were investigated in another 30 Cynomolgus monkeys, and the cells were repeatedly administrated at doses of 3 × 10⁶ cells/kg and 2 × 10⁷ cells/kg for 5 times on a weekly basis, with a recovery period of 1 months. hUC-MSCs showed no obvious toxic effects in cynomolgus monkeys, except xenogeneic immune rejection to human stem cells. Low level of hUC-MSCs gene at were detected in the peripheral blood of a few animals administered 2 × 10⁷ cells/kg at 30 minutes after the first and last administration, indicating that the hUC-MSCs was not significantly amplified in vivo, indicating itssafety in non-human primate. Our study for the first time verified the safety of long-term use of hUC-MSCs in primates. We have pioneered a technology for the real-time detection of hUC-MSCs in peripheral blood and provide dynamic and rapid monitoring of the distribution characteristics of hUC-MSCs in vivo. Here, we provide data supporting the application of such products for clinical treatment and the application of stem cells in major refractory diseases and regenerative medicine.