Bone marrow-derived mesenchymal stem/stromal cells reverse the sensorial diabetic neuropathy via modulation of spinal neuroinflammatory cascades.
BACKGROUND
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) 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.


METHODS
C57Bl/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.


RESULTS
Diabetic 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.


CONCLUSIONS
The present study described the modulatory effects of MSC on spinal cord neuroinflammation in diabetic mice, suggesting new mechanisms by which MSC can improve DN.
['Evangelista|Afrânio Ferreira|AF|', 'Vannier-Santos|Marcos André|MA|', 'de Assis Silva|Gessica Sabrina|GS|', 'Silva|Daniela Nascimento|DN|', 'Juiz|Paulo José Lima|PJL|', 'Nonaka|Carolina Kymie Vasques|CKV|', 'Dos Santos|Ricardo Ribeiro|RR|', 'Soares|Milena Botelho Pereira|MBP|', 'Villarreal|Cristiane Flora|CF|']
D000818:Animals D016026:Bone Marrow Transplantation D002135:Calcium-Binding Proteins D017077:Culture Media, Conditioned D016207:Cytokines D003929:Diabetic Neuropathies D004195:Disease Models, Animal D049452:Green Fluorescent Proteins D006930:Hyperalgesia D015227:Lipid Peroxidation D008297:Male D059630:Mesenchymal Stem Cells D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D008840:Microfilament Proteins D009043:Motor Activity D009573:Nitrites D012584:Sciatic Nerve D013116:Spinal Cord D013311:Streptozocin
Diabetes Neuroinflammation Spinal cord Sensory neuropathy Galectin-3 Stem cells