Pharmacokinetics and In Vivo Fate of Intra-Articularly Transplanted Human Bone Marrow-Derived Clonal Mesenchymal Stem Cells

Abstract

In this study, we report the pharmacokinetics and in vivo fate of intra-articularly transplanted human mesenchymal stem cells (MSCs) in comparison with those of intravenously administered cells. Bone marrow-derived human clonal mesenchymal stem cells (hcMSCs) were transplanted to nude mice through intravenous or intra-articular routes. The numbers of hcMSCs in blood and tissue samples were measured by the quantitative real-time-polymerase chain reaction (qPCR) with human Alu (hAlu) as a detection marker. Following intra-articular transplantation, the blood levels of hcMSCs peaked 8 h postdose and gradually diminished, showing a 95-fold higher mean residence time than hcMSCs delivered through the intravenous route. Unlike intravenously administered hcMSCs, intra-articularly injected hcMSCs were mainly retained at injection joint sites where their levels 8 h postdose were 116-fold higher than those in muscle tissues. Regardless of injection routes, biodistribution patterns did not significantly differ between normal and osteoarthritis-induced mice. Quantitative analysis using hAlu-specific qPCR revealed that hcMSC levels in joint tissues were significantly higher than those in muscle tissues 120 days postdose. These dramatic differences in kinetic behavior and fate of intra-articularly transplanted hcMSCs compared with intravenously administered hcMSCs may provide insights useful for the development of human MSCs for arthritis therapeutics.

A physiologically based kinetic model for elucidating the in vivo distribution of administered mesenchymal stem cells

“…As shown in Fig. 4A,C,D , the model adequately predicted the MSC concentrations in blood in normal mice from the dataset of Shim et al 22 , and MSC concentrations in lung and heart in normal mice from the dataset of Lee et al 7 . However, as shown in Fig.…”

“…Another reason is that mechanistic considerations, such as cell aggregation, changes in flow to organs, were not included in modeling, while these mechanisms might become more relevant to MSC distribution when higher concentration are administered. In the dataset from Shim et al 22 , the distribution of MSCs did not differ significantly between normal and osteoarthritis-induced mice. However, the model underestimated the MSC concentration in the heart with myocardial infarction from the dataset of Lee et al 7 ( Fig.…”

“…The validity of the PBK model was first evaluated with data from Shim et al 22 and Lee et al 7 where MSCs (5 × 10 5 and 2 × 10 6 cells) were intravenously administered to normal and diseased mice. All physiological parameters and MSC-specific parameters in the model were maintained constant.…”

“…The predictive capability of our PBK model was evaluated with external datasets from different species 7 21 22 26 27 . To facilitate comparisons among the various studies, all concentrations were normalized to the number of MSCs per kg of organ.…”

“… ( A ) Mice were intravenously injected with 5 × 10 5 MSCs 22 ( n = 5). ( B–D ) Mice were intravenously injected with 2 × 10 6 MSCs 7 ( n = 6).…”