Umbilical mesenchymal stem cell-derived exosomes facilitate spinal cord functional recovery through the miR-199a-3p/145-5p-mediated NGF/TrkA signaling pathway in rats

Abstract

Background Although exosomes, as byproducts of human umbilical cord mesenchymal stem cells (hUC-MSCs), have been demonstrated to be an effective therapy for traumatic spinal cord injury (SCI), their mechanism of action remains unclear. Methods We designed and performed this study to determine whether exosomes attenuate the lesion size of SCI by ameliorating neuronal injury induced by a secondary inflammatory storm and promoting neurite outgrowth. We determined the absolute levels of all exosomal miRNAs and investigated the potential mechanisms of action of miR-199a-3p/145-5p in inducing neurite outgrowth in vivo and in vitro. Results miR-199a-3p/145-5p, which are relatively highly expressed miRNAs in exosomes, promoted PC12 cell differentiation suppressed by lipopolysaccharide (LPS) in vitro through modulation of the NGF/TrkA pathway. We also demonstrated that Cblb was a direct target of miR-199a-3p and that Cbl was a direct target of miR-145-5p. Cblb and Cbl gene knockdown resulted in significantly decreased TrkA ubiquitination levels, subsequently activating the NGF/TrkA downstream pathways Akt and Erk. Conversely, overexpression of Cblb and Cbl was associated with significantly increased TrkA ubiquitination level, subsequently inactivating the NGF/TrkA downstream pathways Akt and Erk. Western blot and coimmunoprecipitation assays confirmed the direct interaction between TrkA and Cblb and TrkA and Cbl. In an in vivo experiment, exosomal miR-199a-3p/145-5p was found to upregulate TrkA expression at the lesion site and also promote locomotor function in SCI rats. Conclusions In summary, our study showed that exosomes transferring miR-199a-3p/145-5p into neurons in SCI rats affected TrkA ubiquitination and promoted the NGF/TrkA signaling pathway, indicating that hUC-MSC-derived exosomes may be a promising treatment strategy for SCI.

Hyperoside Attenuate Inflammation in HT22 Cells via Upregulating SIRT1 to Activities Wnt/β-Catenin and Sonic Hedgehog Pathways

“…NGF is a nerve cell growth regulator with dual biological functions of neuron nutrition and neurite outgrowth promotion. It has been proven to protect neurons by promoting nerve fiber regeneration [ 36 , 37 ]. Previous studies have shown that LPS-induced inflammation is the main cause of neuronal death in the hippocampus.…”

News about Therapies of Alzheimer’s Disease: Extracellular Vesicles from Stem Cells Exhibit Advantages Compared to Other Treatments

“…MSC-EV fusions have been shown to play critical roles in the intercommunications among brain cells, occurring during health and in various pathologies ( Table 1 ). Numerous protective results have been reported, including development of synaptic plasticity, nutritional metabolic support, nerve regeneration, inflammatory response, and elimination of toxic components [ 46 , 57 ]. Traumas and ischemic lesions can be induced in both the brain and spinal cord.…”

“…Traumas and ischemic lesions can be induced in both the brain and spinal cord. In many cases, the recovery induced by low doses of MSC-EVs has been shown to start with activation of few receptors, followed by phosphorylation of kinases and various factors, and by activation of miRNAs [ 56 , 57 , 58 , 59 ]. Analogously, MSC-EVs have been shown to mitigate trained immune responses induced by innate cells, with distinct local repair [ 60 ].…”

Therapeutic Effect of Exosomes Derived From Stem Cells in Spinal Cord Injury: A Systematic Review Based on Animal Studies

“…Among the included 32 studies, only two studies were controlled studies (29,33), and the remaining 30 studies were randomized controlled studies. The species of animals included SD rats (19-21, 28-37, 39, 40, 42-44, 46, 47, 49-53, 55, 56), Wistar rats (41,54), and C57BL/6 mice (38,45,48); gender included male (28, 30-32, 38-45, 49, 53, 54) and female (19, 20, 29, 33, 34, 36, 37, 46-48, 50-52, 55, 56), two studies did not report the sex of the animals (21,35); the weights of animals were between 150 (41) and 300 g (20,44), the weight of the mouse was between 17 and 22 g ( 48), and seven of the studies did not report the weight of the animals (21,29,30,38,42,45,50); age was between 6 (38,44,45,50,51) and 12 weeks (47, 56), and nine of the studies did not report the age of the animals (19, 21, 35-37, 42, 46, 51, 52); samples size were between 10 (51) and 100 (41); models of SCI included contusion (20, 21, 28-32, 34-53, 56), hemisection (54), and transection (19,33,55); the types of exosomes included the exosomes of bone marrow mesenchymal stem cells of SD rats (BMSCs-Exo) (20, 21, 28, 30, 34-37, 39, 42-44, 47, 49, 52, 53, 56), BMSCs-Exo of Wistar rats (41,54), BMSCs-Exo of human (19,33,…”