Define Mesenchymal Stem Cell from Its Fate: Biodisposition of Human Mesenchymal Stem Cells in Normal and Concanavalin A-Induced Liver Injury Mice

Abstract

The pharmaceutical industry and clinical trials have been revolutionized mesenchymal stem cell-based therapeutics. However, the pharmacokinetics of transplanted cells has been little characterized in their target tissues under healthy or disease condition. A quantitative polymerase chain reaction analytical method with matrix effect was developed to track the biodistribution of human mesenchymal stem cells in normal mice and those with Concanavalin A (Con A)-induced liver injury. Mesenchymal stem/stromal cell (MSC) disposition in blood and different organs were compared, and relevant pharmacokinetic parameters were calculated. Human MSCs (hMSCs) and mouse MSCs (mMSCs) displayed a very similar pharmacokinetic profile in all tested doses: about 95% of the detected hMSCs accumulated in the lung and 3% in the liver, and almost negligible cells were detected in other tissues. A significant double peak of hMSC concentration emerged in the lung within 1-2 hours after intravenous injection, as with mMSCs. Prazosin, a vasodilator, could eliminate the second peak in the lung and increase its C_max and area under the concentration-time curve (AUC) by 10% in the first 2 hours. The injury caused by Con A was significantly reduced by hMSCs, and the C_max and AUC_0-8 (AUC from time 0 to 8 hours) of cells in the injured liver decreased by 54 and 50%, respectively. The C_max and AUC would be improved with the alleviation of congestion through the administration of heparin. The study provides a novel insight into the pharmacokinetics of exogenous MSCs in normal and Con A-induced liver injury mice, which provides a framework for optimizing cell transplantation. SIGNIFICANCE STATEMENT: Mesenchymal stem/stromal cells (MSCs) are known for their potential as regenerative therapies in treating several diseases, but an insufficient understanding of the pharmacokinetics of MSCs restricts their future application. The current study was the first to elucidate the pharmacokinetics and possible factors, including dosage, species, and derived sources, in a systematic way. The study further revealed that Concanavalin A-induced liver injury significantly prevented cells from entering the injury site, which could be reversed by the diminished congestion achieved by heparin.