Dissecting the Pharmacodynamics and Pharmacokinetics of MSCs to Overcome Limitations in Their Clinical Translation

Abstract

Recently, mesenchymal stromal stem cells (MSCs) have been proposed as therapeutic agents because of their promising preclinical features and good safety profile. However, their introduction into clinical practice has been associated with a suboptimal therapeutic profile. In this review, we address the biodistribution of MSCs in preclinical studies with a focus on the current understanding of the pharmacodynamics (PD) and pharmacokinetics (PK) of MSCs as key aspects to overcome unsatisfactory clinical benefits of MSC application. Beginning with evidence of MSC biodistribution and highlighting PK and PD factors, a new PK-PD model is also proposed. According to this theory, MSCs and their released factors are key players in PK, and the efficacy biomarkers are considered relevant for PD in more predictive preclinical investigations. Accounting for the PK-PD relationship in MSC translational research and proposing new models combined with better biodistribution studies could allow realization of the promise of more robust MSC clinical translation.

Challenges in Clinical Development of Mesenchymal Stromal/Stem Cells: Concise Review

“…Along the same line, it has been demonstrated that infused apoptotic MSCs can act together with monocytes to promote immunosuppression in an animal model of graft versus host disease . Collectively, MSC‐based pharmacological developments are still missing robust pharmacodynamic and pharmacokinetic models to be applied in the different clinical situations . This surely calls for ad hoc investigations able to reflect the complexity of these cell types, their interactions with host cells and diseases in which they are applied.…”

Improving preclinical studies through replications

“…This can be combined with experiments that gather converging and discriminant evidence to identify mechanistic underpinnings of an intervention to increase translational validity and identify limitations and boundary conditions. For example, studies of pharmacodynamics and kinetics in preclinical models support in-depth understanding of physiological processes and allow comparison with human pharmacological processes ( Salvadori et al, 2019 ; Tuntland et al, 2014 ).…”

Extracellular Vesicle-Dependent Communication Between Mesenchymal Stromal Cells and Immune Effector Cells

“…MSC systemic administration, which must follow Good Manufacturing Practice (GMP) rules, is not associated to a significant evidence of cell engraftment even in presence of clinical benefit, due to the entrapment of MSCs in the microvasculature of filter organs, such as lungs (Moll et al, 2016;Salvadori et al, 2019). Other biology aspects can interfere with therapeutic efficacy of MSCs.…”