Background: Mesenchymal stem cells (MSCs) present a promising tool in cell therapy for the treatment of various diseases, such as liver cirrhosis. However, their biological fate in the body after administration, which is crucial in the prediction and evaluation of the therapeutic efficacy, has still been poorly understood so far.

Aims: To quantitatively analyze biological fate of MSCs with modeling to better identify the barriers to MSCs delivery, and to propose designs of new formulations and dosing regimens.

Methods: We introduced stable GFP-expressing mouse MSCs into BALB/c nude mice intravenously to mimic the stem cell-based therapy for patients. The in vivo fate of MSCs in major organs was real-time monitored using multiphoton microscopy (MPM). Animals were sacrificed at designated times, and MSCs in the blood and major organs were counted using flow cytometry. A physiologically based kinetic (PBK) model was developed to characterize the physiological processes of administrated MSCs based on the MPM details.

Results: Our PBK model successfully described the concentration-time profiles of MSCs in blood and various organs in mice. This model was validated with multiple external datasets, indicating robust inter-route and inter-species predictive capability. The clinical utility of this model was tested with data obtained from stem cell-based therapies to patients with liver cirrhosis. Our results suggest that the targeting efficiency of MSCs is determined by the redistribution from the lung and their arrest, depletion and release rate in target organs.

Conclusions: We present the first model for characterizing and predicting the biological fate of MSCs precisely. It can be used to scale-up mouse data to predict the kinetics and distribution of MSCs in humans. This novel method provides a general framework for the study of biological fate of therapeutic cells to design treatment protocols and to guide future experiments.