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bone marrow ( bm ) contains populations of precursors that are multipotent and have the characteristics of stem cells of nonhematopoietic tissues .
the precursors of nonhematopoietic tissues are referred to as bone marrow stromal cells ( bmscs ) or mesenchymal stem cells ( mscs ) .
they have attracted interest because of their capacity for self - renewal in a number of nonhematopoietic tissues and their multipotentiality for differentiation .
they are able to cross the blood - brain barrier , to migrate throughout forebrain and cerebellum , and to differentiate to some extent into astrocytes and neurons . despite their transdifferentiation potential
, recent data have shown that mscs display a significant capacity of decreasing inflammation , modulating immune responses , and protecting tissues from injuries , mostly through bystander paracrine mechanisms .  
cellular therapy of brain injury , including stroke and anoxic damage , stemmed from the assumption that stem cells differentiate and replace dead cells .
however , the usefulness of these cells in rebuilding neural networks is controversial , and several studies have now provided significant evidence that other mechanisms are likely to play a major role in protection and neural repair .
these include induction of neurogenesis   and oligodendrogenesis , production of trophic factors , and protection from apoptosis   and from oxidative stress   possibly exerting an anti - inflammatory effect on cells of the innate immunity such as microglia   and macrophages .
regardless of the mechanisms of tissue protection , several data exist concerning the effects of stem cells in the experimental therapy of focal cerebral ischemia [ 6 , 1114 ] , but little research has been done in global cerebral ischemia , although encouraging data exist for this model , too . in the present study , we tested the hypothesis that mscs administered intravenously reduce histological damage after global cerebral ischemia in rats .
our hypothesis in using these cells for the treatment of global cerebral ischemia was that after crossing the blood - brain barrier mscs preferentially reach the damaged areas in the brain [ 15 , 16 ] and are able to produce cytokines and factors that can be used to reduce apoptosis and promote tissue recovery .
the experimental model we choose is the  two - vessel occlusion  ( 2vo ) . in this model , reversible high - grade forebrain ischemia
while techniques using selected arterial occlusion better reproduce the ischemia seen in human stroke , this model of global cerebral ischemia causes a brain damage similar to that observed in patients following , for example , cardiorespiratory arrest . to evaluate the damage induced by global brain ischemia
these cells are selectively vulnerable to global ischemic damage and can therefore gauge the effects of such a damage .
murine bone marrow - derived mscs were isolated from 6- to 8-week - old c57bl/6j mice ( harlan , s. pietro al natisone , italy ) as described elsewhere . in brief ,
marrow cells , flushed out of tibias and femurs , were plated in 75  cm tissue culture flasks ( sarstedt , numbrecht , germany ) at the concentration of 0,3 to 0,4  10 cells / cm using murine mesencult as medium ( stem cell technologies , vancouver , british columbia , canada ) .
cells were cultured in plastic plates as adherent cells and kept in a humidified 5% co2 incubator at 37c , refreshing medium every 3 days for about 6 weeks when cells reached 80% confluence . on treatment with 0.05% trypsin solution containing 0.02% edta ( sigma - aldrich , st . louis , mo ) ,
marrow cells were plated in 25  cm flasks at 1.2 to 2.0  10 cells / cm for the subsequent 4 or 5 passages .
thereafter , cells were routinely seeded at 4 to 10  10 cells / cm .  
mature mscs , obtained after four to five passages in culture , were defined by the expression on their surface of cd9 , sca-1 , cd73 , and cd44 antibodies and by the lack of the hematopoietic markers cd45 , cd34 , and cd11b .
human bone marrow samples were obtained from healthy donors undergoing bone marrow explant for allogeneic transplantation procedures as described elsewhere .
briefly , bone marrow mononuclear cells were isolated by density gradient centrifugation ( 1,077  g / ml ; lympholyte cell separation media , cedar lane , hornby , on , canada ) and seeded at the density of 2530  10 cells per 75  cm tissue culture flasks in human mesencult as medium ( stem cell technologies , vancouver , british columbia , canada ) and incubated at 37c and 5% co2 . at 80% confluence ,
cells were harvested with 0.05% trypsin and 0.02% edta and plated in   75  cm flasks at the density of   7  10 cells .
typical cd34 , cd45 , cd14 , cd73 + , cd44 + , and cd105 + cells were usually obtained after three passages in culture .
adult male sprague - dawley rats weighing 270300  g were obtained from harlan italy san pietro al natisone , udine , italy .
the animals were fasted during the night preceding the operation with free access to water .
anesthesia was induced with   isoflurane ( 5% induction , 1 - 2% maintenance ) in a mixture of n2o and o2   ( 50  :  50 ) by a face mask .
transient global ischemia was induced by bilateral occlusions of the common carotid arteries for 20 minutes .
ischemia duration was calculated as previously reported , leading to a reproducible neuronal damage in the ca1 region of the hippocampus , cortical layers 3 , 5 , and 6 and the basal ganglia .
briefly , both femoral arteries and right femoral vein were exposed and catheterized with teflon catheters .
the left femoral artery was connected to a pressure transducer ( spectramed statham p23xl , viggo - spectramed , oxnard , ca , usa ) providing a recording of arterial pressure through a grass preamplifier , model 7p14a ( grass instruments , quincy , ma , usa ) , for continuous recording of arterial pressure .
the reversible forebrain ischemia was induced by combination of bilateral carotid artery clamping and reduction of mean arterial blood pressure .
the carotid arteries were occluded with stainless microvascular clamps when blood pressure had reached 30  mmhg and then maintained at 30  1  mmhg by blood withdrawal or reinfusion by the cannula in the right femoral artery .
ischemia was terminated after 20 minutes by removal of carotid clamps and by reinfusion of plasma volume expander ( untreated ischemic , n = 4 ) or of 1ml of either   human or murine msc bolus   ( 3  10  msc / ml saline ) ( treated ischemic ,
3 rats represented the sham - operated group ; they were subjected to the surgical procedures except the ischemia and the pressure control .  
after the procedure , each rat recovered in a heated chamber for 2 hours then was returned to a light- and temperature - controlled facility .
five days after ischemia , animals were anaesthetized with urethane ( 150  mg/100  g bw ip ) and transcardially perfused with saline followed by fixation with ice - cold 4% paraformaldehyde in phosphate buffer .
the brains were postfixed in ice - cold 4% paraformaldehyde for one hour then cryoprotected in 30% sucrose .
coronal cryostat sections ( 8  m ) were mounted onto poly - l - lysine - coated slides .
hematoxylin - eosin - stained sections were used to assess the extent of ischemic damage .
20 coronal sections were taken between 3.8 and 3.96  mm posterior to the bregma .
the neuronal count was made under a light microscope at 20x magnification in 12 randomly selected hippocampal sections of 1,7  10  m in the ca1 region .
the number of neurons exhibiting ischemic cell change and morphologically normal neurons was counted in each selected hippocampal section .
ischemic neurons were defined by an intense , darkly stained pyknotic nucleus , surrounded by eosinophilic cytoplasm .
statistical analysis was carried out with analysis of variance ( anova ) followed by bonferroni 's multiple comparison test .
all computations were done using the program graphpad prism , version 4.03 for windows , by graphpad software , san diego california ( usa ) .
data were obtained from 10 rats , treated as follows : 3 sham - operated , 4 ischemic untreated , 2 ischemic treated with human mscs , and 1 ischemic treated with mouse mscs .
since all msc - treated rats showed superimposable results ( see table 1 ) , their data were pooled for further statistical analysis .  
figure 1 shows representative examples of microphotographs of pyramidal neurons of ca1 hippocampal   region of sham - operated ( a ) , ischemic - untreated ( b ) , and ischemic msc - treated rats ( c ) .
average neuronal count ( cells / field ) in the ca1 hippocampal region was ( mean  sd ) 72.05  0.88 for sham - operated rats ( n = 3 ) , 32  9 for untreated ischemic rats ( n = 4 ) , and 56  5 for msc - treated ischemic rats ( n = 3 ) .  
analysis of variance shows a statistically significant difference , and post hoc tests show that all 3 groups are statistically different from each other . as expected , ischemic - untreated rats were worse than sham - operated ones ( p < .001 ) .
ischemic msc - treated rats were better than ischemic untreated , having a significantly higher number of surviving cells ( p < .01 )
. however , count of surviving neurons in ischemic msc - treated rats was lower than in sham - operated rats ( p < .05 ) , thus showing that msc treatment did not cause a total protection of the ischemic neurons .
the present study investigated the therapeutic potential of mscs in a rat model of diffuse neuronal damage induced by global ischemia .
our results suggest that intravenously injected mscs have a positive effect on neuronal survival in this type of neuronal damage .
in fact , we showed that the number of surviving neurons in the ca1 region of the hippocampus of ischemic , msc - treated rats is significantly higher than that of ischemic , untreated ones .
as a word of caution , msc - treated rats were still worse than fully normal ( sham - operated ) animals , thus showing that this therapy , albeit effective , does not cause a full protection of the tissue .
as for the mechanisms that improve ischemic damage upon mscs injection after global ischemia , our data do not directly address the mechanisms responsible for the therapeutic effects of intravenous administration of bone marrow cells on cerebral infarction .
one possibility may be that the msc integrate into the tissue and replace damaged cells ; however , the short time elapsed from ischemia to assessment ( 5 days ) makes it , in our opinion , very unlikely .
despite the fact that a longer observation could have allowed to detect any further improvement due to the possible long - term capacity of providing tissue repair in the ischemic brain , the lack of evidence of engraftment in this study and , more important , the large body of evidence arising from the current literature [ 1 , 3 ] suggest that , msc transdifferentiation into neural cells does not play a major role in brain tissue repair . since the reconstruction of neural circuitry is not always essential for functional recovery ,
a more reasonable hypothesis is that msc therapeutic effect is based on bystander mechanisms leading to tissue protection and repair .
in particular , msc intravenous administration has been shown to lead to production of trophic factors [ 6 , 24 ] , which may be the functional consequence of inflammatory , hypoxic , and oxidative stress - associated insults . moreover ,
msc in vivo administration results also in the downregulation of several stress - associated molecules involved in oxidative stress detoxification .
all these features are supported by the global gene expression profile of therapeutic mscs , which is enriched by anti - inflammatory , antiapoptotic , and trophic genes .
the results provided in this study confirm that mscs are endowed with a remarkable therapeutic plasticity potentially useful for a vast range of diseases sustained by multiple pathogenic mechanisms .
due to their known safety in humans , further studies could expand pioneer experience with mscs in stroke .
although many studies have shown that administration of stem cells after focal cerebral ischemia improves brain damage , very little data are available concerning the damage induced by global cerebral ischemia . 
 the latter causes neuronal death in selectively vulnerable areas , including the hippocampal ca1 region . 
 we tested the hypothesis that intravenous infusion of bone marrowderived stromal cells ( mesenchimal stem cells , msc ) reduce brain damage after transient global ischemia . in adult male sprague - dawley rats transient global ischemia 
 was induced using bilateral common carotid artery occlusion for 20  min in addition to controlled hypotension . 
 five days after , the animals were anaesthetized with urethane and the brain was fixed , sectioned and stained with hematoxylin - eosin to investigate histological damage . 
 msc did not fully protect against ischemic damage , as the number of viable neurons in this group was lower than in normal ( sham - operated ) rats . 
 however , in msc - treated rats the number of viable ca1 pyramidal neurons was significally higher than in rats that had been subjected to ischemia but not treated with msc . 
 we conclude that intravenous administration of msc after transient global ischemia reduces hippocampal damage .