Enhancing Functional Recovery Through Intralesional Application of Extracellular Vesicles in a Rat Model of Traumatic Spinal Cord Injury

Abstract

Local inflammation plays a pivotal role in the process of secondary damage after spinal cord injury. We recently reported that acute intravenous application of extracellular vesicles (EVs) secreted by human umbilical cord mesenchymal stromal cells dampens the induction of inflammatory processes following traumatic spinal cord injury. However, systemic application of EVs is associated with delayed delivery to the site of injury and the necessity for high doses to reach therapeutic levels locally. To resolve these two constraints, we injected EVs directly at the lesion site acutely after spinal cord injury. We report here that intralesional application of EVs resulted in a more robust improvement of motor recovery, assessed with the BBB score and sub-score, as compared to the intravenous delivery. Moreover, the intralesional application was more potent in reducing inflammation and scarring after spinal cord injury than intravenous administration. Hence, the development of EV-based therapy for spinal cord injury should aim at an early application of vesicles close to the lesion.

Small extracellular vesicles derived from mesenchymal stem cell facilitate functional recovery in spinal cord injury by activating neural stem cells via the ERK1/2 pathway

“…Collectively, these results suggested that hucMSC-sEVs effectively improved the symptoms of SCI. In this respect, our experimental results are consistent with previous studies ( Huang et al, 2021 ; Romanelli et al, 2021 ). Next, we explored the underlying mechanism from a novel perspective.…”

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications

“…They observed that such local application drastically lowered the levels of inflammatory cytokines like IL-18, TNF, and others and improved the structural deformities by increasing parenchyma ratios of the spinal cord. 300 An increase in glutamate levels and glutamate-induced neurotoxicity is known in the TBI models. 301 Bone marrow-derived-MSCs exosomes (BM-MSCs-EVs), when cocultured with astrocytes, significantly reduced neurotoxicity upon glutamate treatment by increasing the glutamate transporter-1 (GLT-1) level and a corresponding decrease of the p-p38 MAPK level in the astrocytes.…”

“…As a follow-up, the authors increased the local concentration of the hUC-MSCs-EVs by intralesional delivery in the injury model. They observed that such local application drastically lowered the levels of inflammatory cytokines like IL-18, TNF, and others and improved the structural deformities by increasing parenchyma ratios of the spinal cord . An increase in glutamate levels and glutamate-induced neurotoxicity is known in the TBI models .…”

Evaluation of the Potential of Umbilical Cord Mesenchymal Stromal Cell–Derived Small Extracellular Vesicles to Improve Rotator Cuff Healing: A Pilot Ovine Study

“…Recently, Romanelli et al 35 demonstrated that the local application of a comparable preparation of hUC-MSC-sEVs improved the long-term functional outcomes in a rat model of acute spinal cord injury by attenuating inflammation and reducing local tissue fibrosis. In another study, it was shown that the injection of sEVs (200 µg) harvested from unprimed hUC-MSCs effectively ameliorated tendon adhesion in a rat Achilles tendon injury model.…”

“…3 Here and in previous studies, we demonstrated the suppressive capacity of hUC-MSC-sEVs to inhibit T-cell proliferation in vitro 31 and to attenuate inflammation in vivo. 35 Although our understanding of the therapeutically active components of hUC-MSC-sEVs remains fragmentary, the anti-inflammatory effects elicited by sEVs appear to contribute to improved tissue repair. Along these lines, MRI 6 weeks after surgery indicated less residual inflammation at the site of injury after treatment with hUC-MSC-sEV.…”