Multipotent mesenchymal stromal cells attenuate chronic inflammation and injury-induced sensitivity to mechanical stimuli in experimental spinal cord injury

Abstract

Purpose: Previous reports established that after a contusion injury to the rat spinal cord, locomotor function was enhanced by the transplantation of cells from bone marrow referred to as either mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs). It has also been established that neural stem cells (NSCs) enhance locomotor function after transplantation into the injured rat spinal cord. However, the beneficial effects of NSCs are limited by graft-induced allodynia-like responses. Little is known about the effects of MSCs on sensory function in spinal cord injury. Therefore, the objective of this research was to determine whether transplantation of MSCs into the injured rat spinal cord induces allodynia-like responses. Methods: Contusion injuries of two different severities were induced in rats to examine the effects of transplantation with MSCs on sensorimotor deficits. The effects of MSCs on chronic inflammation were investigated, since inflammation is reported to have a role in the sensorimotor deficits associated with spinal cord injury. In addition, observations in other models suggest that MSCs possess immunosuppressive effects. Results: We found that in contrast to previous observations with the transplantation of neural stem cells, transplantation of MSCs did not induce allodynia. MSCs attenuated injury-induced sensitivity to mechanical stimuli but had no effect on injury-induced sensitivity to cold stimuli. MSCs also significantly attenuated the chronic inflammatory response as assayed by GFAP immunoreactivity for reactive astrocytes and ED1 immunoreactivity for activated macrophages/microglia. In addition, transplantation of MSCs increased white matter volumes and decreased cyst size in sections of the cord containing the lesion. Conclusion: The results suggest that the sensorimotor enhancements produced by MSCs can at least in part be explained by anti-inflammatory/immunosuppressive effects of the cells, similar to such effects of these cells observed in other experimental models.

Bone Marrow Mesenchymal Stem-Cell Transplantation Promotes Functional Improvement Associated with CNTF-STAT3 Activation after Hemi-Sectioned Spinal Cord Injury in Tree Shrews

“…The mechanisms underlying the ability of BMSCs to promote functional remodeling after SCI are likely related to the anti-proliferative and anti-apoptotic proprieties of these cells, which exert anti-inflammatory and immunosuppressive effects at the injury site; additionally, BMSCs induce the repair of nerve cells, promote axonal regeneration, and restore nerve trophism by secreting NTFs (Ohta et al, 2004; Neuhuber et al, 2005; Abrams et al, 2009; Sakata et al, 2011; Tran et al, 2011; Uccelli et al, 2011; Xia et al, 2014; Abbaszadeh et al, 2015; Han et al, 2015). These effects translate into functional improvement, as a study using a dog model of SCI demonstrated that both autologous and allogenic BMSC transplantation improved neurological function following SCI and noted that these improvements were associated with reduced interleukin-6 (IL-6) and cyclooxygenase-2 levels (Jung et al, 2009; Ryu et al, 2012).…”

Meta-analysis of stem cell transplantation for reflex hypersensitivity after spinal cord injury

“…After a literature search conducted electronically and manually, the search strategy initially yielded 20 studies that met inclusion criteria (Abrams et al, 2009; Amemori et al, 2013, 2015; Biernaskie et al, 2007; Choi et al, 2013; Dagci et al, 2011; Furuya et al, 2009; Hofstetter et al, 2005; Karimi-Abdolrezaee et al, 2010; Kumagai et al, 2013; Lee et al, 2007; Macias et al, 2006; Nutt et al, 2013; Ritfeld et al, 2012; Salewski et al, 2015; Tao et al, 2013; Urdzikova et al, 2014; Watanabe et al, 2015; Yao et al, 2015; Yousefifard et al, 2016). These articles were retrieved for further assessment of titles, abstracts, and full-texts (if necessary).…”

“…Of these articles, we excluded seven (Biernaskie et al, 2007; Dagci et al, 2011; Hofstetter et al, 2005; Karimi-Abdolrezaee et al, 2010; Macias et al, 2006; Nutt et al, 2013) that did not measure mechanical withdrawal threshold by the “up and down” von Frey method or measured thermal withdrawal threshold by the tail-flick test. Another was excluded (Abrams et al, 2009) based on exclusion criteria, leaving a total of 12 eligible articles for further assessment (Nutt et al, 2013). Of these, nine reported mechanical withdrawal threshold, and nine reported thermal withdrawal latency (some studies measured only one or the other, and some measured both; Fig.…”

“…However, alleviation of pain in SCI-NP patients by stem cell therapies remains contentious. Some researchers have shown that transplantation of MSCs has positive effects and does not induce allodynia (Abrams et al, 2009; Furuya et al, 2009; Ritfeld et al, 2012; Watanabe et al, 2015). On the other hand, Kumagai et al (2013)) reported that naïve MSCs failed to promote functional recovery and reduce hypersensitivity after contusive SCI.…”

Erythropoietin facilitates the recruitment of bone marrow mesenchymal stem cells to sites of spinal cord injury

“…In order to overcome these restrictions, a number of strategies have been applied, including stimulating neuronal differentiation prior to grafting, neurotrophic gene transfection, co-administration of glial cells and histological engineering (28–30). In a previous study, genetically engineered human BMSCs injected above and below the SCI site in rats immediately following SCI significantly ameliorated subsequent locomotor function (31).…”