Influence of intrathecal delivery of bone marrow-derived mesenchymal stem cells on spinal inflammation and pain hypersensitivity in a rat model of peripheral nerve injury

Abstract

BackgroundMultipotent mesenchymal stem (stromal) cells (MSCs) have been credited with immunomodulative properties, supporting beneficial outcomes when transplanted into a variety of disease models involving inflammation. Potential mechanisms include the secretion of paracrine factors and the establishment of a neurotrophic microenvironment. To test the hypothesis that MSCs release soluble mediators that can attenuate local inflammation, we here analysed the influence of MSCs on the activation of microglia cells, as well as on inflammatory parameters and pain behaviour in a surgical rat model of neuropathic pain.MethodsWe focussed on an experimental model of partial sciatic nerve ligation (PSNL), characterised by a rapid and persistent inflammation in the dorsal lumbar spinal cord where sensory inputs from the sciatic nerve are processed. Via indwelling intrathecal catheters, MSCs were repetitively grafted into the intrathecal lumbar space. Animals were evaluated for mechanical and thermal hypersensitivity over a period of 21 days after PSNL. Afterwards, spinal cords were processed for immunohistochemical analysis of the microglial marker ionized calcium-binding adapter molecule 1 (Iba1) and quantification of inflammatory markers in ipsilateral dorsal horns. We hypothesised that injections on postsurgical days 2 to 4 would interfere with microglial activation, leading to a reduced production of pro-inflammatory cytokines and amelioration of pain behaviour.ResultsPSNL-induced mechanical allodynia or heat hyperalgesia were not influenced by MSC transplantation, and spinal cord inflammatory processes remained largely unaffected. Indeed, the early microglial response to PSNL characterised by increased Iba1 expression in the lumbar dorsal horn was not significantly altered and cytokine levels in the spinal cord at 21 days after surgery were similar to those found in vehicle-injected animals. Grafted MSCs were detected close to the pia mater, but were absent within the spinal cord parenchyma.ConclusionsWe conclude that intrathecal administration is not an appropriate route to deliver cells for treatment of acute spinal cord inflammation as it leads to entrapment of grafted cells within the pia mater. We propose that the early inflammatory response triggered by PSNL in the lumbar spinal cord failed to effectively recruit MSCs or was insufficient to disturb the tissue integrity so as to allow MSCs to penetrate the spinal cord parenchyma.

The Effect of Bone Marrow–Derived Mesenchymal Stem Cell Transplantation on Allodynia and Hyperalgesia in Neuropathic Animals: A Systematic Review with Meta-Analysis

“…Of these, 136 potentially relevant papers were screened. Finally, 13 full-text articles were included for the meta-analysis and were studied in detail [6,[22][23][24][33][34][35][36][37][38][39][40][41] (Table 1). In addition, 1 eligible unpublished set of data, which were obtained from an experiment in our lab, were included in the analysis (unpublished data, F. Nasirinezhad, July 2015).…”

“…Of the 14 articles, 4 reported only the impact of BMMSCs transplantation on hyperalgesia [22,35,39,40] and 4 assessed its effect on allodynia [23,33,34,41]. Six articles evaluated the effect on both [6,24,[36][37][38].…”

“…These studies have lacked a proper randomized control group and have been underpowered. However, a substantial number of controlled preclinical studies have investigated the effect of BMMSCs on neuropathic pain [6,[22][23][24][33][34][35][36][37][38][39][40][41]. These studies revealed various degrees of improvement of neuropathic pain and symptoms, such as allodynia and hyperalgesia.…”

Intravenously Infusing the Secretome of Adipose-Derived Mesenchymal Stem Cells Ameliorates Neuroinflammation and Neurological Functioning After Traumatic Brain Injury

“…Cell-based therapies have exhibited great advantages in terms of treating central nervous system (CNS) diseases such as stroke [10,11], Alzheimer's disease [12], and TBI [13,14]. It has been confirmed that mesenchymal stem cells (MSCs) serve as regulators of inflammation by secreting a large number of cytokines that maintain milieu interne stability [15]. By releasing anti-inflammatory factors such as prostaglandin E2 (PGE2) [16], tumor necrosis factorstimulated gene 6 protein (TSG-6) [17], and transforming growth factor (TGF)-b1 [18], MSCs promote resident microglia to polarize into the M2 phenotype and alleviate further proinflammatory reactions [19].…”

Effect of mesenchymal stem cells transplantation combining with hyperbaric oxygen therapy on rehabilitation of rat spinal cord injury

“…Neuroinflammation is a pathological process principally involving activation of microglia and astrocytes by inflammatory mediators in various CNS disorders, including brain trauma, ischemia, and SCI [3,4] . To date, there is still lack of effective therapy to treat traumatic SCI.…”