Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges

Abstract

Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.

Fig. 1

Multiple steps in mesenchymal stem cells (MSCs) homing. The homing processes of MSCs are dependent on a series of molecules of motile potency, including selectins, integrins, chemokine receptors, and proteases. Selectins, which are expressed on endothelial cells (ECs), capture MSCs by interacting with their ligands and then mediating the rolling of MSCs. MSCs can thus be activated by exposure to chemokines, consequently leading to integrin-dependent firm adhesion to the endothelium. At the appropriate location, MSCs cross the endothelial barrier by secreting different proteases before continuing chemokine-mediated migration

Fig. 2

Regulators and effects of different MSC fates. Regulated by a variety of intrinsic or extrinsic factors, MSCs develop into different destinies. MSCs have stem cell properties and diverse differentiation directions under distinct conditions. Phagocytosis of MSCs is mediated mostly by the monocyte‒macrophage system. Autophagy and senescence can be activated in ROS-enriched environments or under other conditions. Many MSCs undergo apoptosis. Changes in the functions and phenotypes of MSCs and their consequent effects can be detected when MSCs progress to different fates

Fig. 3

Multimodal tracing strategies for MSCs in vivo. Precise and effective detection methods are vital for exploring the migration and distribution of mesenchymal stem cells (MSCs). Currently, there are various detection techniques available. Nuclear imaging tracks the biodistribution of cells by imaging radiolabeled tracers. Optical imaging, including bioluminescence imaging (BLI) and fluorescence imaging (FLI), plays an important role in researching the biodistribution of MSCs in different disease models. Cell tracking with magnetic resonance imaging (MRI) requires labeling cells with contrast agents. Magnetic particle imaging (MPI) can detect nanoparticle tracers at any time and location in the body with greater spatial and temporal resolution than MRI. Ultrasound imaging and photoacoustic imaging are noninvasive and emerging imaging modalities. The development of multiple-modality imaging is an emerging trend in MSC tracking and clinical research

Fig. 4

Druggability of MSCs. Applying the right treatment to the appropriate population, in the correct dosage regimen, and at the appropriate time is the most crucial principle in the druggability process of MSCs. The biodistribution and fate of MSCs at different time points were monitored by various imaging technologies. These parameters were combined with pharmacodynamic data to construct a PK/PD model of MSCs. Prediction of the pharmacokinetic properties of MSCs in patients, appropriate dosage regimens, and individualized treatments can be achieved with the PK/PD model. Therefore, the most crucial step in the druggability of MSCs is constructing an appropriate treatment regimen based on the pharmacokinetic and pharmacodynamic properties of MSCs