Modeling of Modulated Exosome Release From Differentiated Induced Neural Stem Cells for Targeted Drug Delivery

Abstract

A novel implantable and externally controllable stem-cell-based platform for the treatment of Glioblastoma brain cancer has been proposed to bring hope to patients who suffer from this devastating cancer type. Induced Neural Stem Cells (iNSCs), known to have potent therapeutic effects through exosomes-based molecular communication, play a pivotal role in this platform. Transplanted iNSCs demonstrate long-term survival and differentiation into neurons and glia which then fully functionally integrate with the existing neural network. Recent studies have shown that specific types of calcium channels in differentiated neurons and astrocytes are inhibited or activated upon cell depolarization leading to the increased intracellular calcium concentration levels which, in turn, interact with mobilization of multivesicular bodies and exosomal release. In order to provide a platform towards treating brain cancer with the optimum therapy dosage, we propose mathematical models to compute the therapeutic exosomal release rate that is modulated by cell stimulation patterns applied from the external wearable device. This study serves as an initial and required step in the evaluation of controlled exosomal secretion and release via induced stimulation with electromagnetic, optical and/or ultrasonic waves.

A Neuron-Glial Model of Exosomal Release in the Onset and Progression of Alzheimer's Disease

“…The calcium-mediated exosomal release is restricted to active zones that contain VGCCs that control Ca 2+ from the extracellular domain, mediate and regulate exocytosis, leading to the exosomal release in the brain (Veletić et al, 2020 ). This mechanism can be conveniently modeled by combining the Watts-Sherman model for Ca 2+ exosomal release and the Montefusco-Pedersen models for Ca 2+ -regulated exocytosis, as originally put forth by Veletić et al ( 2020 ).…”

“…The calcium-mediated exosomal release is restricted to active zones that contain VGCCs that control Ca 2+ from the extracellular domain, mediate and regulate exocytosis, leading to the exosomal release in the brain (Veletić et al, 2020 ). This mechanism can be conveniently modeled by combining the Watts-Sherman model for Ca 2+ exosomal release and the Montefusco-Pedersen models for Ca 2+ -regulated exocytosis, as originally put forth by Veletić et al ( 2020 ). To link neuronal electrical activity and Ca 2+ -mediated exocytosis, we first describe intracellular Ca 2+ dynamics, paying special attention to microdomain Ca 2+ concentrations surrounding high-voltage activated L-type Ca 2+ channels ( C L ) when the channels are opened ( C L | opened ) and closed ( C L | closed ), low-voltage activated T-type Ca 2+ channels, as well as the characterization of Ca 2+ below the plasma membrane ( C m ) in the bulk cytosol ( C c ), and in the endoplasmic reticulum ( C r ).…”

“…where is the Hill function, C L | closed = C m (Montefusco and Pedersen, 2015 ), and the collective exosomal release rate in neurons is given by Veletić et al ( 2020 ):…”

“…The whole-cell intracellular Ca 2+ dynamics ensues from the mass balance of Ca 2+ fluxes across four different compartments: (i) C L ; (ii) C m ; (iii) C c and (iv) C r . The equations for compartment-specific Ca 2+ concentrations (Veletić et al, 2020 ):…”

Visualizing Extracellular Vesicles and Their Function in 3D Tumor Microenvironment Models

“…The EV-based MC models complement models from computational biology and create a new in-silico approach in analyzing EV-mediated signaling. Input/output analyses are envisioned to predict EV-associated cell response to the chemical, electrical or mechanical factors, replacing in vitro experiments [ 177 ]. Metrics such as information channel capacity, error probability, throughput and latency can further provide an in-depth analysis of EV signaling pathways and, for example, optimize EV dosage and the efficacy of the EV-based therapy [ 178 ].…”