Abstract
BackgroundDiabetic neuropathy (DN) is a frequent and debilitating manifestation of diabetes mellitus, to which there are no effective therapeutic approaches. Mesenchymal stem/stromal cells (MSC) have a great potential for the treatment of this syndrome, possibly through regenerative actions on peripheral nerves. Here, we evaluated the therapeutic effects of MSC on spinal neuroinflammation, as well as on ultrastructural aspects of the peripheral nerve in DN-associated sensorial dysfunction.MethodsC57Bl/6 mice were treated with bone marrow-derived MSC (1 × 106), conditioned medium from MSC cultures (CM-MSC) or vehicle by endovenous route following the onset of streptozotocin (STZ)-induced diabetes. Paw mechanical and thermal nociceptive thresholds were evaluated by using von Frey filaments and Hargreaves test, respectively. Morphological and morphometric analysis of the sciatic nerve was performed by light microscopy and transmission electron microscopy. Mediators and markers of neuroinflammation in the spinal cord were measured by radioimmunoassay, real-time PCR, and immunofluorescence analyses.ResultsDiabetic mice presented behavioral signs of sensory neuropathy, mechanical allodynia, and heat hypoalgesia, which were completely reversed by a single administration of MSC or CM-MSC. The ultrastructural analysis of the sciatic nerve showed that diabetic mice exhibited morphological and morphometric alterations, considered hallmarks of DN, such as degenerative changes in axons and myelin sheath, and reduced area and density of unmyelinated fibers. In MSC-treated mice, these structural alterations were markedly less commonly observed and/or less pronounced. Moreover, MSC transplantation inhibited multiple parameters of spinal neuroinflammation found in diabetic mice, causing the reduction of activated astrocytes and microglia, oxidative stress signals, galectin-3, IL-1β, and TNF-α production. Conversely, MSC increased the levels of anti-inflammatory cytokines, IL-10, and TGF-β.ConclusionsThe present study described the modulatory effects of MSC on spinal cord neuroinflammation in diabetic mice, suggesting new mechanisms by which MSC can improve DN.
Highlights
Diabetic neuropathy (DN) is a frequent and debilitating manifestation of diabetes mellitus, to which there are no effective therapeutic approaches
Mesenchymal stem/stromal cells (MSC) transplantation reduces the sensorial dysfunction in diabetic neuropathic mice Behavioral testing was performed at baseline and daily, after the model induction, to evaluate the effects of MSC transplantation on measurable sensorial parameters of STZ-induced diabetic neuropathy
STZ treatment induced sensory neuropathy associated with mechanical allodynia (Fig. 1a) and heat hypoalgesia in mice (Fig. 1b), without causing motor impairment, as assessed by the rota-rod test
Summary
Diabetic neuropathy (DN) is a frequent and debilitating manifestation of diabetes mellitus, to which there are no effective therapeutic approaches. We evaluated the therapeutic effects of MSC on spinal neuroinflammation, as well as on ultrastructural aspects of the peripheral nerve in DN-associated sensorial dysfunction. Diabetes mellitus is a highly debilitating disease that affects humans, with an estimated global prevalence of 6% [1]. Clinical manifestations of DN include painful neuropathic symptoms, such as spontaneous pain, hyperalgesia and allodynia, and sensory loss, resulting in foot ulcerations and amputations [4]. The available analgesic drugs appear to be relatively ineffective in controlling neuropathic pain associated with DN [5]. There are no drugs available that can restore nerve function, and the usual therapeutic strategies for diabetic neuropathic pain are limited to palliative analgesic effects [6]
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