Mesenchymal stem cells derived extracellular vesicles improve behavioral and biochemical deficits in a phencyclidine model of schizophrenia

Hadas Tsivion-Visbord,Angela Ruban,Lior Bikovski,Nisim Perets,Daniel Offen,Tamar Sofer,Yona Goldshmit

doi:10.1038/s41398-020-00988-y

Hadas Tsivion-Visbord, Angela Ruban + Show 5 more

Open Access

https://doi.org/10.1038/s41398-020-00988-y

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Abstract

Schizophrenia is a debilitating psychiatric disorder with a significant number of patients not adequately responding to treatment. Phencyclidine (PCP) is used as a validated model for schizophrenia, shown to reliably induce positive, negative and cognitive-like behaviors in rodents. It was previously shown in our lab that behavioral phenotypes of PCP-treated mice can be alleviated after intracranial transplantation of mesenchymal stem cells (MSC). Here, we assessed the feasibility of intranasal delivery of MSCs-derived-extracellular vesicles (EVs) to alleviate schizophrenia-like behaviors in a PCP model of schizophrenia. As MSCs-derived EVs were already shown to concentrate at the site of lesion in the brain, we determined that in PCP induced injury the EVs migrate to the prefrontal cortex (PFC) of treated mice, a most involved area of the brain in schizophrenia. We show that intranasal delivery of MSC-EVs improve social interaction and disruption in prepulse inhibition (PPI) seen in PCP-treated mice. In addition, immunohistochemical studies demonstrate that the EVs preserve the number of parvalbumin-positive GABAergic interneurons in the PFC of treated mice. Finally, MSCs-EVs reduced glutamate levels in the CSF of PCP-treated mice, which might explain the reduction of toxicity. In conclusion, we show that MSCs-EVs improve the core schizophrenia-like behavior and biochemical markers of schizophrenia and might be used as a novel treatment for this incurable disorder.

Highlights

Schizophrenia is a severe psychiatric disorder, ranked by the World Health Organization as one of the top ten illnesses contributing to the global health burden of disease[1]
In the current study we have shown that intranasal treatment with extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC) can improve schizophrenia-like behaviors and biochemical properties in a protect against phencyclidine (PCP) mice model
In this study we demonstrate that, delivered by an intranasal approach, MSCs-EVs constitute a marked improvement for therapy in a schizophrenia model

Summary

Introduction

Schizophrenia is a severe psychiatric disorder, ranked by the World Health Organization as one of the top ten illnesses contributing to the global health burden of disease[1]. Major areas of disability are largely divided into positive, negative and cognitive symptoms. Roughly a third of patients do not respond well to antipsychotics and are considered treatment-resistant[5,6], while responders frequently suffer adverse effects, such as weight gain and dyslipidemia, which may result in severe deterioration of health after long-term treatment[7]. This underlines the fact that adequate therapies are still sorely lacking for this disorder

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