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

Abstract

Hemi-sectioned spinal cord injury (hSCI) can lead to spastic paralysis on the injured side, as well as flaccid paralysis on the contralateral side, which can negatively affect a patient’s daily life. Stem-cell therapy may offer an effective treatment option for individuals with hSCI. To examine the role of bone marrow mesenchymal stem cells (BMSCs) transplantation on hSCI and explore related mechanisms in the tree shrews, here, we created a model of hSCI by inducing injury at the tenth thoracic vertebra (T10). Hoechst 33342-labeled BMSCs derived from adult tree shrews were isolated, cultured, and implanted into the spinal cord around the injury site at 9 days after injury. The isolated BMSCs were able to survive, proliferate and release a variety of neurotrophic factors (NTFs) both in vitro and in vivo. At 28 days after injury, compared with the sham group, the hSCI group displayed scar formation and dramatic elevations in the mean interleukin 1 beta (IL-1β) density and cell apoptosis level, whereas the expression of signal transducer and activator of transcription 3 (STAT3) and ciliary neurotrophic factor (CNTF) mRNA was reduced. Following BMSC transplantation, motoneurons extent of shrinkage were reduced and the animals’ Basso, Beattie, and Bresnahan (BBB) locomotion scale scores were significantly higher at 21 and 28 days after injury when compared with the injured group. Moreover, the hSCI-induced elevations in scar formation, IL-1β, and cell apoptosis were reduced by BMSC transplantation to levels that were close to those of the sham group. Corresponding elevations in the expression of STAT3 and CNTF mRNA were observed in the hSCI + BMSCs group, and the levels were not significantly different from those observed in the sham group. Together, our results support that grafted BMSCs can significantly improve locomotor function in tree shrews subjected to hSCI and that this improvement is associated with the upregulation of CNTF and STAT3 signaling.

Anti-inflammatory protein TSG-6 secreted by bone marrow mesenchymal stem cells attenuates neuropathic pain by inhibiting the TLR2/MyD88/NF-κB signaling pathway in spinal microglia

“…Consistent with our results, previous studies demonstrated that intrathecal delivery of BMSCs can relieve neuropathic pain and that the analgesic effect of BMSCs persists for at least 14 days [34,35]. Mesenchymal stem-cell therapy, such as BMSCs treatment, has been considered a potentially successful approach for treating various diseases including neuropathic pain [37,46], spinal cord injury [47,48], Alzheimer's disease [49,50], stroke [51,52], and lung injury [53,54]. BMSCs were the earliest and the most widely studied MSCs in vitro and in vivo.…”

Abdominal Aortic Transplantation of Bone Marrow Mesenchymal Stem Cells Regulates the Expression of Ciliary Neurotrophic Factor and Inflammatory Cytokines in a Rat Model of Spinal Cord Ischemia-Reperfusion Injury

“…Previous studies have shown that BMMSCs could induce neural cell repair by secreting neurotrophic factors, promoting axonal regeneration leading to functional improvement following spinal cord injury [ 7 – 9 ]. In this study, immunohistochemistry showed that on day 7 after surgery, the transplanted BMMSCs could significantly reduce neuronal necrosis in the spinal cord of the ischemic segments, and increase the number of normal neurons.…”

“…Bone marrow mesenchymal stem cells (BMMSCs) have the advantages of ease of availability, a reduced risk of immune rejection, multipotential cell differentiation, and multiple transplantation pathways, which make them ideal tissue engineering and transplant stem cells, which can also be used in arterial and aortic transplantation [ 6 ]. Transplanted BMMSCs have been shown to secrete a variety of neurotrophic factors, which exert a synergistic neuroprotective effect with exogenous neurotrophic factors [ 7 – 9 ]. In a previous study, BMMSCs have been shown to express and secrete ciliary neurotrophic factor (CNTF) in vitro [ 10 ].…”

Cytokines in Scar Glial Formation after an Acute and Chronic Spinal Cord Injury

“…The implantation of BMSCs has shown to have regenerative and immunomodulative properties that help to prevent the GS formation [91]. Furthermore, these cells are able to regulate CNTF-STAT3 signal transduction which reduces tissue scarring, inflammatory responses, and apoptosis [92]. Okuda et al reported that BMSC sheets suppress the GS and provide a positive environment for axonal regeneration, causing changes in reactive astrocyte morphology [93].…”