Functional Recovery Caused by Human Adipose Tissue Mesenchymal Stem Cell-Derived Extracellular Vesicles Administered 24 h after Stroke in Rats

Abstract

Ischemic stroke is a major cause of death and disability, intensely demanding innovative and accessible therapeutic strategies. Approaches presenting a prolonged period for therapeutic intervention and new treatment administration routes are promising tools for stroke treatment. Here, we evaluated the potential neuroprotective properties of nasally administered human adipose tissue mesenchymal stem cell (hAT-MSC)-derived extracellular vesicles (EVs) obtained from healthy individuals who underwent liposuction. After a single intranasal EV (200 µg/kg) administered 24 h after a focal permanent ischemic stroke in rats, a higher number of EVs, improvement of the blood–brain barrier, and re-stabilization of vascularization were observed in the recoverable peri-infarct zone, as well as a significant decrease in infarct volume. In addition, EV treatment recovered long-term motor (front paws symmetry) and behavioral impairment (short- and long-term memory and anxiety-like behavior) induced by ischemic stroke. In line with these findings, our work highlights hAT-MSC-derived EVs as a promising therapeutic strategy for stroke.

Poststroke Intravenous Transplantation of Human Mesenchymal Stem Cells Improves Brain Repair Dynamics and Functional Outcomes in Aged Mice

“…35 In addition to bone marrow-derived MSCs, EVs from adipose-derived MSCs also exert positive effects on the reconstruction of blood vessels and functional recovery in the adult brain. 36 Wide availability of MSC-EVs from different tissues provides additional options for MSC-EV administration in humans. Compared with intravenous infusions of hMSCs, intranasal administration of EVs is less invasive.…”

“…Compared with intravenous infusions of hMSCs, intranasal administration of EVs is less invasive. 36 Thus, we think MSCs-EVs could be a promising therapeutic strategy that mimics the effect of MSCs transplantation.…”

Current Status of Mesenchymal Stem/Stromal Cells for Treatment of Neurological Diseases

“…MSC-derived products have already been tested in stroke models. Intranasal injection of human AT-MSC-derived Evs 24 h after a thermocoagulation ischemic lesion-induced a reduction in infarct volume and re-stabilization of vascularization in the peri-infarct area, culminating in behavioral improvement (Rohden et al, 2021 ). Recently, Zhao et al ( 2020 ) showed that exosomes isolated from rat BM-MSCs overexpressing microRNA-223-3p injected into the tail vein 24 h and 14 days after MCAO induced an improvement in NSS, in relation to naïve-BM-MSC exosomes, but both groups were significantly different from the vehicle.…”

Recommendation: Treatment of clinical long COVID encephalopathies with nasal administered mesenchymal stromal cell extracellular vesicles

“…This has included studies in ischemic and hemorrhagic strokes (Xin et al, 2013a;Xin et al, 2013b;Doeppner et al, 2015a;Chen et al, 2016;Otero-Ortega et al, 2017;Venkat et al, 2019;Mahdavipour et al, 2020;Rohden et al, 2021) and perinatal brain injury (Drommelschmidt et al, 2017;Sisa et al, 2019;Kaminski et al, 2020), some treated with intranasal MSC-EVs (Thomi et al, 2019a;Thomi et al, 2019b). Importantly, for this discussion regarding nasal sEV therapy of the neuro-psychiatric aspects of LCS, this includes the treatment of various neurodegenerative diseases with nasal sEVs, that has succeeded in diminishing pathologies in animal models of Parkinson's disease (Laso-Garcia et al, 2018;Clark et al, 2019;Narbute et al, 2019;Chen et al, 2020;Jafarinia et al, 2020;Zhu et al, 2021), amyotrophic lateral sclerosis (ALS) (Bonafede et al, 2016;Gugliandolo et al, 2019), and Alzheimer's disease (Alvarez-Erviti et al, 2011;Ding et al, 2018a;Elia et al, 2019;Reza-Zaldivar et al, 2019;Losurdo et al, 2020a;Ma et al, 2020a;Cone et al, 2021a); as well as psychiatric disorders such as autism (Perets et al, 2018;Alessio et al, 2020) and schizophrenia (Tsivion-Visbord et al, 2020), and further in neurotraumas such as traumatic brain injury (Patel et al, 2018;Ni et al, 2019;Williams et al, 2019;Sun et al, 2020;Williams et al, 2020), spinal cord injury …”