WJSC 6^(th) Anniversary Special Issues(2):Mesenchymal stem cells Mesenchymal stem cells in the treatment of spinal cord injuries:A review

With technological advances in basic research,the intricate mechanism of secondary delayed spinal cord injury(SCI)continues to unravel at a rapid pace.However,despite our deeper understanding of the molecular changes occurring after initial insult to the spinal cord,the cure for paralysis remains elusive.Current treatment of SCI is limited to early administration of high dose steroids to mitigate the harmful effect of cord edema that occurs after SCI and to reduce the cascade of secondary delayed SCI.R ecent evident-based clinical studies have cast doubt on the clinical benefit of steroids in SCI and intense focus on stem cell-based therapy has yielded some encouraging results.An array of mesenchymal stem cells(MSCs)from various sources with novel and promising strategies are being developed to improve function after SCI.In this review,we briefly discuss the pathophysiology of spinal cord injuries and characteristics and the potential sources of MSCs that can be used in the treatment of SCI.We will discuss the progress of MSCs application in research,focusing on the neuroprotective properties of MSCs.Finally,we will discuss the results from preclinical and clinical trials involving stem cell-based therapy in SCI.

Stem cell treatment improves post stroke neurological outcomes:a comparative study in male and female rats

Background and purpose The therapeutic potential of different stem cells for ischaemic stroke treatment is intriguing and somewhat controversial.Recent results from our laboratory have demonstrated the potential benefits of human umbilical cord blood-derived mesenchymal stem cells(MSC)in a rodent stroke model.We hypothesised that MSC treatment would effectively promote the recovery of sensory and motor function in both males and females,despite any apparent sex differences in post stroke brain injury.Methods Transient focal cerebral ischaemia was induced in adult Sprague-Dawley rats by occlusion of the middle cerebral artery.Following the procedure,male and female rats of the untreated group were euthanised 1 day after reperfusion and their brains were used to estimate the resulting infarct volume and tissue swelling.Additional groups of stroke-induced male and female rats were treated with MSC or vehicle and were subsequently subjected to a battery of standard neurological/neurobehavioral tests(Modified Neurological Severity Score assessment,adhesive tape removal,beam walk and rotarod).The tests were administered at regular intervals(at days 1,3,5,7 and 14)after reperfusion to determine the time course of neurological and functional recovery after stroke.Results The infarct volume and extent of swelling of the ischaemic brain were similar in males and females.Despite similar pathological stroke lesions,the clinical manifestations of stroke were more pronounced in males than females,as indicated by the neurological scores and other tests.MSC treatment significantly improved the recovery of sensory and motor function in both sexes,and it demonstrated efficacy in both moderate stroke(females)and severe stroke(males).Conclusions Despite sex differences in the severity of post stroke outcomes,MSC treatment promoted the recovery of sensory and motor function in male and female rats,suggesting that it may be a promising treatment for stroke.

Post-stroke mRNA expression profile of MMPs:effect of genetic deletion of MMP-12

background and purpose Recent reports from our laboratory demonstrated the post-ischaemic expression profile of various matrix metalloproteinases(MMPs)in rats and the detrimental role of MMP-12 in post-stroke brain damage.We hypothesise that the post-stroke dysregulation of MMPs is similar across species and that genetic deletion of MMP-12 would not affect the post-stroke expression of other MMPs.We tested our hypothesis by determining the pre-ischaemic and post-ischaemic expression profile of MMPs in wild-type and MMP-12 knockout mice.Methods Focal cerebral ischaemia was induced in wildtype and MMP-12 knockout mice by middle cerebral artery occlusion procedure by insertion of a monofilament suture.One hour after ischaemia,reperfusion was initiated by removing the monofilament.One day after reperfusion,ischaemic brain tissues from various groups of mice were collected,and total RNA was isolated and subjected to cDNA synthesis followed by PCR analysis.results Although the post-stroke expression profile of MMPs in the ischaemic brain of mice is different from rats,there is a clear species similarity in the expression of MMP-12,which was found to be predominantly upregulated in both species.Further,the post-stroke induction or inhibition of various MMPs in MMP-12 knockout mice is different from their respective expression profile in wild-type mice.Moreover,the brain mRNA expression profile of various MMPs in MMP-12 knockout mice under normal conditions is also different to their expression in wild-type mice.Conclusions In the ischaemic brain,MMP-12 upregulates several fold higher than any other MMP.Mice derived with the genetic deletion of MMP-12 are constitutive and have altered MMP expression profile both under normal and ischaemic conditions.

Implications of MMP-12 in the pathophysiology of ischaemic stroke

This article focuses on the emerging role of matrix metalloproteinase-12(MMP-12)in ischaemic stroke(IS).MMP-12 expression in the brain increases dramatically in animal models of IS,and its suppression reduces brain damage and promotes neurological,sensorimotor and cognitive functional outcomes.Thus,MMP-12 could represent a potential target for the management of IS.This article provides an overview of MMP-12 upregulation in the brain following IS,its deleterious role in the post-stroke pathogenesis(blood-brain barrier disruption,inflammation,apoptosis and demyelination),possible molecular interactions and mechanistic insights,its involvement in post-ischaemic functional deficits and recovery as well as the limitations,perspectives,challenges and future directions for further research.Prior to testing any MMP-12-targeted therapy in patients with acute IS,additional research is needed to establish the effectiveness of MMP-12 suppression against IS in older animals and in animals with comorbidities.This article also examines the clinical implications of suppressing MMP-12 alone or in combination with MMP-9 for extending the currently limited tissue plasminogen activator therapy time window.Targeting of MMP-12 is expected to have a profound influence on the therapeutic management of IS in the future.