Exosomes Derived From Schwann Cells Ameliorate Peripheral Neuropathy in Type 2 Diabetic Mice

Abstract

Schwann cell-derived exosomes communicate with dorsal root ganglia (DRG) neurons. The current study investigated the therapeutic effect of exosomes derived from healthy Schwann cells (SC-Exos) on diabetic peripheral neuropathy (DPN). We found that intravenous administration of SC-Exos to type 2 diabetic db/db mice with peripheral neuropathy remarkably ameliorated DPN by improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity. These functional improvements were associated with the augmentation of epidermal nerve fibers and remyelination of sciatic nerves. Quantitative RT-PCR and Western blot analysis of sciatic nerve tissues showed that SC-Exo treatment reversed diabetes-reduced mature form of miRNA (miR)-21, -27a, and -146a and diabetes-increased semaphorin 6A (SEMA6A); Ras homolog gene family, member A (RhoA); phosphatase and tensin homolog (PTEN); and nuclear factor-kB (NF-kB). In vitro data showed that SC-Exos promoted neurite outgrowth of diabetic DRG neurons and migration of Schwann cells challenged by high glucose. Collectively, these novel data provide evidence that SC-Exos have a therapeutic effect on DPN in mice and suggest that SC-Exo modulation of miRs contributes to this therapy.

Emerging Roles of microRNAs as Biomarkers and Therapeutic Targets for Diabetic Neuropathy

“…In a preclinical study, Lopez-Verrilli et al reported that Schwann cell-derived exosomes were internalized by DRG axons to promote axonal regeneration (123). Our group showed that exosomes derived from Schwann cells (SC-exos) increased intraepidermal nerve fiber density in the footpad and reduced axonal and myelin damage of the sciatic nerve, leading to a reduction of neuropathic symptoms in DN mice (124). In contrast, exosomes derived from Schwann cells cultured in highglucose medium facilitated the development of DN by reducing epidermal nerve fibers (125).…”

The Role of Semaphorins in Metabolic Disorders

“…Exosomes derived from healthy Schwann cells (SC-Exos) show therapeutic effects for type 2 diabetic peripheral neuropathy by improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity. Western blot analysis of sciatic nerve tissues showed that the DPN considerably increased Sema6A expression, whereas the SC-Exos treatment, significantly reduced Sema6A expression, suggesting that Sema6A could contribute to DPN [112].…”

“…Nrp1, Nrp2 [108,109] Sema3A Not mentioned [110,111] Sema6A Not mentioned [112] Diabetic wound healing Sema4D PlexinB2 [113] Sema6A Not mentioned [114] Diabetic osteoporosis Sema3A Not mentioned [115][116][117][118]…”

Exosome: A New Player in Translational Nanomedicine

“…Exosomes can be produced by the vast majority of cells with different origins and numerous functions. The cells from which exosomes are secreted include T cells [73,74], platelets [75], megakaryocytes [76] mast cells [77,78], neurons [79,80], oligodendrocytes [81] and Schwann cells [82][83][84][85]. Similarly, cells with stemness properties, such as mesenchymal stromal cells (MSCs) [86][87][88] and induced pluripotent stem cells (iPSCs) [89,90], have been reported to release exosomes.…”