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

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.

Mesenchymal stem cells: Cell therapy and regeneration potential

“…Wang, Ma, et al, 2018) Bone and cartilage diseases (Jo et al, 2014;Kastrinaki et al, 2013) Autoimmune diseases (Xu, 2018;W. Zhang, Feng, et al, 2018) Amyotrophic lateral sclerosis (Bonafede & Mariotti, 2017) Diabetes (Evangelista et al, 2018;Gabr et al, 2018) Glaucoma (Manuguerra-Gagne et al, 2013;Osborne, Sanderson, & Martin, 2018;Roubeix et al, 2015) Graft vs host disease (Jurado et al, 2017;Zhao et al, 2015) Intervertebral disc disease (Ahn et al, 2015;Beeravolu et al, 2018;Pereira et al, 2016;Perez-Cruet et al, 2018) Multiple sclerosis (Harris et al, 2018;Nasri et al, 2018;Planchon et al, 2018) Myocardial infarction ( investigated for the treatment of chronic tissue ulcers caused by diabetes. Patients were administered with MSCs for skin healing showed an improvement in microvascularisation structure (Kirana et al, 2012).…”

“…Wang, Zhang, Shen, Zhang, & Gu, 2018;, myocardial infarction (X. Q. Chen et al, 2014), and type 1 diabetes mellitus (Evangelista et al, 2018). It has also been shown that the use of chemokines and cytokines derived from MSCs improved the treatment efficacy for autoimmune disease (M. Wang, Yuan, & Xie, 2018;Xu, 2018;W.…”

Effect of TO901317 on promoting the differentiation of human bone marrow mesenchymal stem cells into dopamine neurons on Parkinson's disease

“…Some studies have shown that BMSCs expressed genes and proteins related with the neural lineage, and have been displayed to hold neurogenic differentiation potential the proper conditions in vitro [44][45][46] . BMSCs transplantation restrained multiple parameters of spinal neuroin ammation found in diabetic mice 47 . BMSCs can release neurotrophic factors, including GDNF and BDNF to protect neurons 48,49 .…”

Therapeutic effect of TO901317 on 6-OHDA-induced Parkinson rats in vitro and in vivo

“…Some studies have shown that BMSCs expressed genes and proteins related with the neural lineage, and have been displayed to hold neurogenic differentiation potential the proper conditions in vitro [40][41][42] . BMSCs transplantation restrained multiple parameters of spinal neuroinflammation found in diabetic mice 43 . It is important that BMSCs can release neurotrophic factors, including GDNF and BDNF to protect neurons 44,45 .…”