Offen’s Lab of Translational Neuroscience
Felsenstein Medical Research Center
Dept. of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine
Sagol School of Neuroscience
Tel Aviv University
Cerebrospinal fluid (CSF)-derived exosomes from patients with parkinson's disease induce parkinson-like symptoms and pathology in mice
Parkinson’s disease (PD) is characterized by the gradual appearance of intraneuronal Lewy aggregates (Lewy bodies), which are primarily composed of misfolded α-synuclein (α-syn), resulting in cytotoxicity and neural death. To examine whether aggregated α-syn can actively spread from the nasal cavity to the brain via exosomes and initiate pathological aggregate in the brain, we isolated exosomes from patient's CSF- PD patients or non-PD patients.
We found that intra nasal delivery of CSF-derived exosomes from PD patients induce impairments in motor behavior, hyposmia, elevated anxiety and gained less weight. These data suggest that exosomes are involved in the propagating α-syn aggregation and in the initiating of PD-like symptoms.
Increased RNA editing in maternal immune activation model of neurodevelopmental disease
We utilized a mouse model of maternal immune activation (MIA) with the viral mimic PolyI:C infection during early gestation and investigated the transcriptional changes in the brains of mouse fetuses following MIA during the prenatal period, and evaluated the behavioral and biochemical changes in the adult brain. The results reveal an increase in RNA editing levels and dysregulation in brain development-related gene pathways in the fetal brains of MIA mice. Our findings suggest that MIA induces transient dysregulation of RNA editing at a critical time in brain development.
Intranasal Delivery of Mesenchymal Stem Cell Derived Exosomes Loaded with Phosphatase and Tensin Homolog siRNA Repairs Complete Spinal Cord Injury
Spontaneous recovery and therapeutic efficacy after spinal cord injury (SCI) are limited. We demonstrate that when given intranasally, exosomes derived from mesenchymal stem cells (MSC-Exo) could pass the blood brain barrier and migrate to the injured spinal cord area. Furthermore, MSC-Exo loaded with phosphatase and tensin homolog small interfering RNA (ExoPTEN) enhanced axonal growth and neovascularization. The intranasal ExoPTEN therapy could also partly improve structural and electrophysiological function and, most importantly, significantly elicited functional recovery in rats with complete SCI.
Intranasal administration of exosomes derived from mesenchymal stem cells ameliorates autistic-like behaviors of BTBR mice
BTBR T+tf/J (BTBR) mice are an accepted model of evaluating behaviors as they present all core symptoms of Autism spectrum disorder (ASD). We have previously shown that transplantation of human bone marrow mesenchymal stem cells (MSC) to the lateral ventricles of BTBR mice results in long lasting improvement in their autistic behavioral phenotypes. Recently we found that intranasal administration of MSC-exo increased male to male social interaction and reduced repetitive behaviors. Moreover, the treatment led to increases of male to female ultrasonic vocalizations and significant improvement in maternal behaviors of pup retrieval. The marked beneficial effects of the exosomes in BTBR mice may translate to a novel, non-invasive, and therapeutic strategy to reduce the symptoms of ASD.