Mesenchymal stromal cell-derived exosomes ameliorate peripheral neuropathy in a mouse model of diabetes

Abstract

Aims/hypothesis Diabetic peripheral neuropathy (DPN) is one of the major complications of diabetes, which contributes greatly to morbidity and mortality. There is currently no effective treatment for this disease. Exosomes are cell-derived nanovesicles and play an important role in intercellular communications. The present study investigated whether mesenchymal stromal cell (MSC)-derived exosomes improve neurological outcomes of DPN. Methods Exosomes were isolated from the medium of cultured mouse MSCs by ultracentrifugation. Diabetic mice (BKS.Cg-m+/+Lepr db /J, db/db) at the age of 20 weeks were used as DPN models. Heterozygous mice (db/m) of the same age were used as the control. MSC-exosomes were administered weekly via the tail vein for 8 weeks. Neurological function was evaluated by testing motor and sensory nerve conduction velocities, and thermal and mechanical sensitivity. Morphometric analysis was performed by myelin sheath staining and immunohistochemistry. Macrophage markers and circulating cytokines were measured by western blot and ELISA. MicroRNA (miRNA) array and bioinformatics analyses were performed to examine the exosomal miRNA profile and miRNA putative target genes involved in DPN. Results Treatment of DPN with MSC-exosomes markedly decreased the threshold for thermal and mechanical stimuli and increased nerve conduction velocity in diabetic mice. Histopathological analysis showed that MSC-exosomes markedly augmented the density of FITC-dextran perfused blood vessels and increased the number of intraepidermal nerve fibres (IENFs), myelin thickness and axonal diameters of sciatic nerves. Western blot analysis revealed that MSC-exosome treatment decreased and increased M1 and M2 macrophage phenotype markers, respectively. Moreover, MSC-exosomes substantially suppressed proinflammatory cytokines. Bioinformatics analysis revealed that MSC-exosomes contained abundant miRNAs that target the Toll-like receptor (TLR)4/NF-κB signalling pathway. Conclusions/interpretation MSC-derived exosomes alleviate neurovascular dysfunction and improve functional recovery in mice with DPN by suppression of proinflammatory genes.

Immunomodulation of MSCs and MSC-Derived Extracellular Vesicles in Osteoarthritis

“…In an experimental murine model of bronchopulmonary dysplasia, MSC-derived EVs ameliorated hyperoxia-associated inflammation via modulation of lung macrophage phenotype (Willis et al, 2018 ). Similar immunoregulatory roles of MSC-derived EVs have been established in inflammatory bowel disease (Schena et al, 2010 ) and diabetic peripheral neuropathy (Fan et al, 2020 ).…”

Diet-Induced Rodent Models of Diabetic Peripheral Neuropathy, Retinopathy and Nephropathy

“…Genetic animal models of T2DM/DPN (e.g., Bio-Breeding Zucker diabetic rat (BBZDR) /Wor rat, Zucker diabetic fatty (ZDF) rat, Goto Kakizaki (GK) rat, db/db mice, ob/ob mice, diabetic black and tan, brachyuric (BTBR) ob/ob mouse) as well as the streptozotocin (STZ) diabetic rodents (40-80 mg STZ/kg body weight, i.p./i.v.) have been available for years and used to study DPN [30][31][32][33][34][35]. Yet, none follow the gradual onset of metabolic imbalances and the natural progression from obesity to T2DM.…”

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