Abstract
Painful neuropathy is one of the complications of diabetes mellitus that adversely affects patients’quality of life. Pharmacological treatments are not fully satisfactory, and novel approaches needed. In a preclinical mouse model of diabetes the effect of both human mesenchymal stromal cells from adipose tissue (hASC) and their conditioned medium (hASC-CM) was evaluated. Diabetes was induced by streptozotocin. After neuropathic hypersensitivity was established, mice were intravenously injected with either 1 × 106 hASC or with CM derived from 2 × 106 hASC. Both hASC and CM (secretome) reversed mechanical, thermal allodynia and thermal hyperalgesia, with a rapid and long lasting effect, maintained up to 12 weeks after treatments. In nerves, dorsal root ganglia and spinal cord of neuropathic mice we determined high IL-1β, IL-6 and TNF-α and low IL-10 levels. Both treatments restored a correct pro/antinflammatory cytokine balance and prevented skin innervation loss. In spleens of streptozotocin-mice, both hASC and hASC-CM re-established Th1/Th2 balance that was shifted to Th1 during diabetes. Blood glucose levels were unaffected although diabetic animals regained weight, and kidney morphology was recovered by treatments. Our data show that hASC and hASC-CM treatments may be promising approaches for diabetic neuropathic pain, and suggest that cell effect is likely mediated by their secretome.
Highlights
Diabetes mellitus (DM) is one of the most common and serious chronic diseases around the world[1] and diabetic peripheral neuropathy is one of the most frequent complications of DM
We previously demonstrated that human ASC treatment reduced both allodynia and hyperalgesia and normalized neuroinflammation in a murine model of neuropathy induced by sciatic nerve chronic constriction injury (CCI)[14]
Diabetic neuropathic pain is characterized by sensory alterations, including hypoaesthesia, tactile and thermal allodynia, and current treatments are often active on only some of them[20]
Summary
Diabetes mellitus (DM) is one of the most common and serious chronic diseases around the world[1] and diabetic peripheral neuropathy is one of the most frequent complications of DM. We and others have demonstrated that pro- and anti-inflammatory cytokines, produced by immune cells as well as by glia and microglia in nerve, dorsal root ganglia and spinal cord, are involved in neuropathic pain[4,5,6]. They start a cascade of neuroinflammation-related events that may maintain and worsen the original injury, participating in pain generation and chronicization[4,5,6,7]. Many studies provide pivotal support for this paracrine hypothesis and MSC therapy is increasingly rationalized on MSC secreted factors rather than on their differentiation ability[15]
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