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

Abstract

Although mesenchymal stem cells (MSCs) present a promising tool in cell therapy for the treatment of various diseases, the in vivo distribution of administered MSCs has still been poorly understood, which hampers the precise prediction and evaluation of their therapeutic efficacy. Here, we developed the first model to characterize the physiological kinetics of administered MSCs based on direct visualization of cell spatiotemporal disposition by intravital microscopy and assessment of cell quantity using flow cytometry. This physiologically based kinetic model was validated with multiple external datasets, indicating potential inter-route and inter-species predictive capability. Our results suggest that the targeting efficiency of MSCs is determined by the lung retention and interaction between MSCs and target organs, including cell arrest, depletion and release. By adapting specific parameters, this model can be easily applied to abnormal conditions or other types of circulating cells for designing treatment protocols and guiding future experiments.

Mesenchymal stromal cell-based therapy: Regulatory and translational aspects in gastroenterology

“…Notably, this analysis allowed to calculate changes in MSC distribution occurring in disease states entailing loss of function of specific organs ( e.g ., heart failure). In line with other studies, supply through the hepatic artery was then suggested as an alternative route of administration to avoid lung overload[23,33]. …”

“…This phenomenon could explain the extremely high percentage of MSCs localized in the lung after intravenous injection[18,26,29]. Recently, mouse models have confirmed the pulmonary localization of MSCs[30-33]. Furthermore, infusion of MSCs led to pulmonary parenchymal edema and hemorrhage at the highest dose tested[34].…”

“…Furthermore, infusion of MSCs led to pulmonary parenchymal edema and hemorrhage at the highest dose tested[34]. Wang and colleagues proposed an in silico approach to predict the time course of the localization of MSCs after intravenous injection in vivo [33]. Notably, this analysis allowed to calculate changes in MSC distribution occurring in disease states entailing loss of function of specific organs ( e.g ., heart failure).…”

Massive computational acceleration by using neural networks to emulate mechanism-based biological models

“…For instance, modeling has been used to examine of the network motifs or the parameter sets able to generate oscillations 15,16 or spatial patterns 17 , or the noise characteristics of signaling networks [18][19][20][21] . They may also serve as the foundation for practical applications, such as designing treatments of diseases [22][23][24] and interpreting the pharmacokinetics of drugs [25][26][27] . Many mechanism-based models cannot be solved analytically and have to be analyzed by numerical methods.…”

Real-time optical imaging of the liver: diagnosis and prediction of treatment response

“…Mesenchymal stem cell (MSC) is one of the most promising and widely used therapeutic cells for many debilitating diseases including liver cirrhosis, diabetes, spinal cord injury and myocardial infarction. Recently, a whole body PBPK model has been developed based on the organ disposition and cell-tissue interactions of GFP-expressing MSCs visualised by MPM [72]. This imaging technique opens up a new window for more in-depth investigation about the disposition of molecules, nanoparticles and biological agents in the liver and other organs to understand their in vivo pharmacokinetics and pharmacodynamics.…”