Therapeutic Effect of Astroglia-like Mesenchymal Stem Cells Expressing Glutamate Transporter in a Genetic Rat Model of Depression

Abstract

Recent studies have proposed that abnormal glutamatergic neurotransmission and glial pathology play an important role in the etiology and manifestation of depression. It was postulated that restoration of normal glutamatergic transmission, by enhancing glutamate uptake, may have a beneficial effect on depression. We examined this hypothesis using unique human glial-like mesenchymal stem cells (MSCs), which in addition to inherent properties of migration to regions of injury and secretion of neurotrophic factors, were differentiated to express high levels of functional glutamate transporters (excitatory amino acid transporters; EAAT). Additionally, gold nanoparticles (GNPs), which serve as contrast agents for CT imaging, were loaded into the cells for non-invasive, real-time imaging and tracking of MSC migration and final location within the brain. MSC-EAAT (2×105; 10 μl) were administered (i.c.v.) to Flinder Sensitive Line rats (FSLs), a genetic model for depression, and longitudinal behavioral and molecular changes were monitored. FSL rats treated with MSC-EAAT showed attenuated depressive-like behaviors (measured by the forced swim test, novelty exploration test and sucrose self-administration paradigm), as compared to controls. CT imaging, Flame Atomic Absorption Spectroscopy analysis and immunohistochemistry showed that the majority of MSCs homed specifically to the dentate gyrus of the hippocampus, a region showing structural brain changes in depression, including loss of glial cells. mRNA and protein levels of EAAT1 and BDNF were significantly elevated in the hippocampus of MSC-EAAT-treated FSLs. Our findings indicate that MSC-EAATs effectively improve depressive-like manifestations, possibly in part by increasing both glutamate uptake and neurotropic factor secretion in the hippocampus.

Intrathecal Infusion of Autologous Adipose-Derived Regenerative Cells in Autoimmune Refractory Epilepsy: Evaluation of Safety and Efficacy

“…13 Stem Cells International our patients. Shwartz's group described similar effect in animal model of depression and connected that with increasing both glutamate uptake and neurotropic factor secretion in the hippocampus [21]. The possible mechanism involved in positive ADRC effect including remission or transient seizure reduction is similar to that in other autoimmune diseases, i.e., lupus erythema or rheumatoid arthritis-immunomodulation and stabilization of the pathological systemic status due to adjuvant MSC properties.…”

Encapsulated stem cells ameliorate depressive-like behavior via growth factor secretion

“…When MSCs are transplanted into the lateral ventricle, they travel to the ipsilateral hippocampus, yet when the hippocampus is targeted for direct injection of MSCs, there are no significant antidepressant effects in rodent depression models. [ 12 13 26 ] Evidence is shown that the administration of eMSCs-LV ameliorates depressive-like behavior, signifying that migration nor transplantation of MSCs into the hippocampus are necessary for the beneficial antidepressant effects to be present.…”

Nanoparticle contrast agents for X‐ray imaging applications

“…Betzer et al (2015) developed a protocol for labeling different types of cells with AuNP for in vivo applications (Figure 8a,b). This technology was applied in various mouse disease models for noninvasive CT monitoring of mesenchymal stem cell (MSC) in brain disorder treatment (Betzer et al, 2014; Shwartz et al, 2017), photoreceptor precursors in retinal replacement therapy (Chemla et al, 2019), and melanoma‐specific T cells in cancer immunotherapy treatment (Figure 8c–f) (Meir et al, 2015). Design principles for cell tracking were further established using CT imaging after intramuscular stem cell transplantation in a mouse model of Duchenne muscular dystrophy.…”