stroke accounts for approximately 11% of all deaths worldwide and is the most common cause of adult - acquired disability . among all stroke cases ,
ischemic stroke and intracerebral hemorrhage ( ich ) account for about 8085% and 1520% , respectively .
intravenous thrombolysis by using tissue plasminogen activator ( tpa ) is the only approved treatment for acute ischemic stroke .
however , tpa has very narrow time window ( within 4.5 h after onset ) of application
. therefore , only a minority of patients ( 2% to 4% ) can receive timely therapy .
cell therapy might be a promising strategy for stroke . bone marrow - derived mononuclear cells ( bm - mncs ) and mesenchymal stem cells ( bm - mscs ) both are bone marrow stromal cells ( bm - scs ) and are most frequently used in preclinical and clinical neurorestorative studies in stroke .
bm - mncs / mscs have self - renewal capacity and pluripotency to differentiate into several mesenchymal cellular lineages , including osteoblasts , chondroblasts , adipocytes , myocytes , and fibroblasts .
they can also differentiate into non - mesenchymal lineages , including neurons and glial cells .
preclinical studies observed that bm - mncs / mscs transplanted either intracranially or intravascularly could migrate to damaged brain tissue and exert a neuroprotection effect by inhibiting apoptosis , decreasing peri - infarct inflammation , and promoting angiogenesis [ 79 ] .
therefore , during the past decade , a series of clinical trials was performed to assess the effectiveness and safety of bm - scs transplantation after stroke .
due to the small number of patients recruited in individual trials , the statistical power of the conclusions is weak .
one recent single - arm meta - analysis showed this cell therapy could effectively improve national institutes of health stroke scale ( nihss ) scores , modified barthel index ( mbi ) score and modified rankin score ( mrs ) .
however , without comparison with a control group , there might have observational bias . therefore ,
this study aimed to pool previous controlled trials to assess the effectiveness of bm - scs - based cell therapy after ischemic stroke .
this study generally followed the preferred reporting items for systematic reviews and meta - analyses ( prisma ) guidelines .
relevant studies published from 1 jan 2000 to 1 sept 2014 were searched among pubmed , medline , embase , and the cochrane database .
we only included randomized or non - randomized controlled trials that assessed effectiveness of bm - mncs / mscs - based cell therapy in either ischemic stroke patients .
the basic data extracted from original studies included : family name of the first author , year of publication , type of stoke , study design , number of patients , mean age , type of cell used , route of cell delivery , number of cells injected , time interval from stroke to therapy , follow - up , baseline nihss score , and outcome indicator measured . to assess the effectiveness of cell therapy , the outcome indicators used to assess therapeutic effectiveness include modified rankin score ( mrs ) , barthel index ( bi ) or modified barthel index ( mbi ) , and national institutes of health stroke scale ( nihss ) .
original data were pooled and analyzed by using review manager 5.3 ( the cochrane collaboration ) .
the risk ratio ( rr ) and corresponding 95% confidence intervals ( ci ) of mrs 2 ( cell therapy vs. control ) were estimated . for the discontinuous data , including bi or mbi and nihss score , weighted mean difference ( wmd ) and corresponding 95% ( ci ) was estimated .
the chi - square based q test and i value were used to assess between - study heterogeneity , which also determines the methods used for making estimation .
the random - effects model ( dersimonian and laird method ) was used when p < 0.1 in q test or i > 50% , which indicates significant heterogeneity .
otherwise , the fixed - effects model based on mantel - haenszel method was applied .
this study generally followed the preferred reporting items for systematic reviews and meta - analyses ( prisma ) guidelines .
relevant studies published from 1 jan 2000 to 1 sept 2014 were searched among pubmed , medline , embase , and the cochrane database .
we only included randomized or non - randomized controlled trials that assessed effectiveness of bm - mncs / mscs - based cell therapy in either ischemic stroke patients .
the basic data extracted from original studies included : family name of the first author , year of publication , type of stoke , study design , number of patients , mean age , type of cell used , route of cell delivery , number of cells injected , time interval from stroke to therapy , follow - up , baseline nihss score , and outcome indicator measured . to assess the effectiveness of cell therapy , the outcome indicators used to assess therapeutic effectiveness include modified rankin score ( mrs ) , barthel index ( bi ) or modified barthel index ( mbi ) , and national institutes of health stroke scale ( nihss ) .
original data were pooled and analyzed by using review manager 5.3 ( the cochrane collaboration ) . the risk ratio ( rr ) and corresponding 95% confidence intervals ( ci ) of mrs 2 ( cell therapy vs. control ) were estimated . for the discontinuous data , including bi or mbi and nihss score , weighted mean difference ( wmd ) and corresponding 95% ( ci ) was estimated .
the chi - square based q test and i value were used to assess between - study heterogeneity , which also determines the methods used for making estimation . the random - effects model ( dersimonian and laird method )
was used when p < 0.1 in q test or i > 50% , which indicates significant heterogeneity .
otherwise , the fixed - effects model based on mantel - haenszel method was applied .
based on searching and screening with the preset criteria , 5 trials [ 1115 ] were finally included in this meta - analysis .
the 5 trials involved a total of 228 patients , among which 104 were in the cell therapy group and 124 were in the control group .
two studies used bm - mscs   and 3 studies used bm - mncs [ 1315 ] .
four studies transplanted cells through iv injection [ 1113,15 ] and 1 used ia injection .
the time interval from stroke to cell therapy varied from several days to several months after stroke .
four trials reported outcome with 6-month follow - up , while 1 study reported 5-year outcome . generally , modified rankin score ( mrs ) , barthel index ( bi ) , modified bi ( mbi ) , and national institutes of health stroke scale ( nihss ) scores are the 3 indicators most used to assess clinical outcomes of cell therapy . two studies reported bi and 2 studies reported mbi at the end of follow - up . generally ,
although the cell therapy group had slightly higher bi or mbi score , the mean difference was not significant between cell therapy and control group ( wmd : 2.50 , 95%ci : 4.69 to 9.68 , p=0.50 , i=46% ) ( figure 2 ) . subgroup analysis was performed by stratifying bi and mbi .
subgroup using mbi as the indicator of daily activities of living reported significantly higher mbi score in the cell therapy group than in the controls ( wmd : 7.44 , 95%ci : 1.82 to 13.06 , p=0.009 , i=0% ) ( figure 2 ) , but no significant difference was observed in the bi subgroup ( wmd : 3.24 , 95%ci : 12.14 to 5.65 , p=0.47 , i=0% ) ( figure 2 ) .
two studies reported nihss at the end of follow - up . generally , the mean difference of nihss score was significant lower in the cell therapy group than in the control group ( wmd : 1.85 , 95%ci : 2.77 to 0.93 , p<0.0001 , i=24% ) ( figure 3 ) .
due to the non - randomized design of some studies , we only compared the proportion of patients with mrs 2 before and after cell therapy in the experimental arm .
the meta - analysis did not find significant change in the proportion of patient in the mrs 2 group before and after cell therapy ( 13/86 vs. 15/86 ) ( rr : 1.81 , 95%ci : 0.37 to 8.95 , p=0.47 ) ( figure 4 ) .
infection , recurrence of stroke , and death were used to assess the safety of bm - mscs transplantation .
our meta - analysis did not find any difference in these 3 indicators between the cell therapy and control group ( figure 5 ) .
two studies reported bi and 2 studies reported mbi at the end of follow - up .
generally , although the cell therapy group had slightly higher bi or mbi score , the mean difference was not significant between cell therapy and control group ( wmd : 2.50 , 95%ci : 4.69 to 9.68 , p=0.50 , i=46% ) ( figure 2 ) .
subgroup using mbi as the indicator of daily activities of living reported significantly higher mbi score in the cell therapy group than in the controls ( wmd : 7.44 , 95%ci : 1.82 to 13.06 , p=0.009 , i=0% ) ( figure 2 ) , but no significant difference was observed in the bi subgroup ( wmd : 3.24 , 95%ci : 12.14 to 5.65 , p=0.47 , i=0% ) ( figure 2 ) .
two studies reported nihss at the end of follow - up . generally , the mean difference of nihss score was significant lower in the cell therapy group than in the control group ( wmd : 1.85 , 95%ci : 2.77 to 0.93 , p<0.0001 , i=24% ) ( figure 3 ) .
three studies reported the change in mrs at the end of follow - up . due to the non - randomized design of some studies , we only compared the proportion of patients with mrs 2 before and after cell therapy in the experimental arm .
the meta - analysis did not find significant change in the proportion of patient in the mrs 2 group before and after cell therapy ( 13/86 vs. 15/86 ) ( rr : 1.81 , 95%ci : 0.37 to 8.95 , p=0.47 ) ( figure 4 ) .
infection , recurrence of stroke , and death were used to assess the safety of bm - mscs transplantation .
our meta - analysis did not find any difference in these 3 indicators between the cell therapy and control group ( figure 5 ) .
in animal models , transplantation of bm - mncs or mscs could reduce inflammation , decrease the infarct size in the brain , and improve neurological function in several models of stroke through multiple mechanisms [ 1618 ] . a recent meta - analysis based on 46 preclinical animal studies
previous preclinical studies observed that although bm - mscs and bm - mncs could transdifferentiate into neuronal - like in vitro , they did not have basic neuronal functional properties ; this transdifferentiation seldom happens in vivo .
in fact , a study based on animal models showed that only a very small proportion ( about 0.02% ) of the intravenously delivered bm - mncs migrate to the ischemic area of the brain , while most of the transplanted cells develop a macrophage / microglial phenotype .
generally , the transplanted cells have a stimulating effect on release of cytokines and neurotrophic factors , including brain - derived neurotrophic factor ( bdnf ) , basic fibroblast growth factor ( bfgf ) , nerve growth factor , vascular endothelial growth factor ( vegf ) , insulin - like growth factor-1 , hepatocyte growth factor ( hgf ) , and stem cell factor .
these factors can induce angiogenesis , reduce neuronal apoptosis , enhance axonal regeneration , rebuild synapses and dendrites , and promote differentiation of endogenous neural stem and progenitor cells .
these effects do not necessarily require the presence of transplanted cells at the injury site in the brain .
therefore , the paracrine effects of transplanted cells might be fundamental to positive clinical outcomes .
however , in clinical trials , data on the exact effects of bm - mncs / mscs - based cell therapy after stroke are still conflicting .
this study , based on 5 double - arms trials , demonstrated that bm - derived stromal cells might have some benefits in lowering the grade of impairment caused by ischemic stroke .
in fact , a 1-point increase of nihss score decreases the likelihood of an excellent outcome by 17% .
in addition , there might be some benefits in activities of daily living as measured by mbi .
however , the studies involved a limited number of patients and were conducted by a same research team , so the statistical power of the finding might be weak .
clinical trials usually define favorable outcome of stroke as mrs grade 2 . however , this meta - analysis failed to demonstrate significant benefits of bm - mscs / mncs - based cell therapy in increasing the proportion of mrs 2 patients . due to
this study did not find any severe adverse events associated with cell therapy , suggesting it is a relatively safe intervention .
firstly , the number of trials and the number of patients recruited in each trial were small .
in addition , different trials reported different clinical outcomes , which makes it hard to use the same scale to summarize the results .
these limitations significantly weaken the statistical power of the findings . secondly , to develop an effective cell therapy strategy , several factors , including eligibility criteria of the patients , timing , and route and dose of cell transplantation , should be considered in clinical practice .
however , based on the available evidence , these factors still need to be optimized .
patients with moderate , but not mild or severe , stroke might be more suitable for cell therapy , since patients with mild strokes generally have uniformly good outcome and patients with severe stroke are less likely to respond to the intervention and thus are unlikely have good outcome . the 5 trials recruited patients with basic nihss scores ranging from 4 to 20 , which means minor , moderate , and moderate - to - severe patients were all recruited . therefore
although bm - mncs / mscs transplantation might generate some benefits in lowering the grade of impairment caused by ischemic stroke , large rcts are required to further confirm the effectiveness of bm - mscs / mncs - based cell therapy and to optimize the conditions required for best therapeutic effects .
 backgroundautologous bone marrow stromal cells ( bm - scs ) transplantation might be a potential therapy for stroke . 
 although a series of clinical trials were performed to assess the effectiveness and safety of bm - scs transplantation after ischemic stroke , the results are still conflicting . this study aimed to pool 
 previous controlled trials to assess the effectiveness of bm - scs - based cell therapy after ischemic stroke.material/methodsrelevant studies were searched among online databases . 
 barthel index ( bi ) or modified barthel index ( mbi ) , national institutes of health stroke scale ( nihss ) , and rankin score ( mrs ) were used to assess therapeutic effects . 
 the frequencies of adverse events were extracted for assessing safety of stem cell therapy . 
 data analysis was performed by using review manager 5.3.resultspatients who received cell therapy had significantly lower nihss score ( 1.85 ) than the controls . 
 in addition , there might be some benefits in daily activity measured by mbi , but this meta - analysis failed to demonstrate significant benefits of bm - scs - based cell therapy in increasing the proportion of mrs 2 patients . 
 we did not find any severe adverse events associated with bm - scs - based cell therapy.conclusionsalthough bm - mncs / mscs transplantation might generate some benefits in lowering the grade of impairment caused by ischemic stroke , large rcts are required to further confirm the effectiveness of bm - mscs / mncs - based cell therapy and to optimize the conditions require for best therapeutic effects . 
Background
Material and Methods
Study search and selection
Data extraction
Statistical analysis
Results
The effect of BM-MSCs on BI or mBI score
The effect of BM-MSCs on NIHSS score
The effect of BM-MSCs on mRS
Safety assessment of BM-MSCs transplantation
Discussion
Conclusions