Bone Marrow Mononuclear Cell Transplantation Research Articles

Transplantation of Bone Marrow Mononuclear Cells Reduces Mortality and Improves Renal Function on Mercury-Induced Kidney Injury in Mice

Objective: Recent studies have demonstrated the therapeutic effects of bone marrow–derived cells in tissue regeneration. The aim of this study was to investigate the effects of bone marrow mononuclear cell (BMMC) transplantation in a mouse model of acute renal failure (ARF) induced by mercuric chloride. Methods: BMMC was isolated from male BALB/c mice and injected into female mice treated with a lethal dose (LD90) of mercuric chloride. Survival rate, histopathological analysis, and assessment of urea, creatinine, sodium, potassium, and mercury levels were carried out. Results: Cellular therapy with BMMC significantly reduced the mortality induced by mercuric chloride (p < 0.05). This finding correlated with a decrease in serum levels of urea (p = 0.04) and potassium (p < 0.01). However, no differences in renal morphology were observed when BMMC-treated and control group were compared. Conclusion: Transplanted BMMC improve renal function and reduce mortality and, therefore, may represent a new therapeutic alternative to treat ARF.

Effect of the bone marrow cell transplantation on elevated plus-maze performance in hippocampal-injured mice

Several reports have shown that the hippocampus plays an important role in different aspects of the emotional control. There is evidence that lesions in this structure cause behavioral disinhibition, with reduction of reactions expressing fear and anxiety. Thus, to portray the aptitude of cell therapy to abrogate injuries of hippocampal tissue, we examined the behavioral effects of bone marrow mononuclear cells (BMMCs) transplantation on C57BL/6 mice that had the hippocampus damaged by electrolytic lesion. For this purpose, mice received, seven days after bilateral electrolytic lesion in the dorsal hippocampus, culture medium or BMMCs expressing the enhanced green fluorescent protein (EGFP) transgene. One week after transplantation, animals were tested in the elevated plus-maze (EPM). On the whole, three assessment sessions in the EPM were carried out, with seven days separating each trial. Thirty-five days after the induction of injury, mice were sacrificed and their brains removed for immunohistochemistry. The behavioral evaluation showed that the hippocampal lesion caused disinhibition, an effect which was slightly lessened, from the second EPM test, in transplanted subjects. On the other hand, immunohistochemical data revealed an insignificant presence of EGFP+ cells inside the brains of injured mice. In view of such scenario, we hypothesized that the subtle rehabilitation of the altered behavior might be a result from a paracrine effect from the transplanted cells. This might have been caused by the release of bioactive factors capable of boosting endogenous recuperative mechanisms for a partial regaining of the hippocampal functions.

A pilot trial of autologous bone marrow mononuclear cell transplantation through grafting artery: A sub-study focused on segmental left ventricular function recovery and scar reduction

Our preliminary study suggested that patients with chronic myocardial infarction (MI) and heart failure could potentially benefit from CABG combined with aBM-MNC by improving global left ventricular (LV) function. The purpose of this sub-study was to quantitatively evaluate the effectiveness of aBM-MNC transplantation during CABG in patients with chronic MI by intensively analyzing the global and segmental LV function, the scar, and the relationships between the function recovery and the scar transmural extent. A randomized, double-blinded, placebo-controlled study was performed in 50 patients with chronic MI. The patients were randomly allocated into CABG with stem cell transplantation (group A) and CABG only (group B) groups. CMR assessments of global and segmental left ventricular function and scar tissue were performed before surgery and repeated at 12 months after CABG and aBM-MNC transplantation. The left ventricular ejection fraction (LVEF) improved by 13.5% and 8.0% in group A and B respectively (P=0.04). Segmental analysis of regional LV function recovery indicated that more improvement in contractility was found in group A within the same degree of the infarct transmurality (P=0.017) and showed a predominant interaction in the most severely affected segments (76-100%, P=0.016). Decrease in infarct size between the two groups did not reach statistical difference (9.4% vs. 6.0%, P=0.100). CMR assessments revealed reversed ventricular remodeling and improved systolic function and scar reduction in patients who underwent aBM-MNC transplantation during CABG. And the conjunctional use of CABG and stem cell therapy could improve the left ventricular function in patients with chronic MI.

Autologous Bone Marrow Mononuclear Cell Transplantation in Patients with Decompensated Alcoholic Liver Disease: A Randomized Controlled Trial

ObjectiveImpaired liver regeneration is associated with a poor outcome in patients with decompensated alcoholic liver disease (ALD). We assessed whether autologous bone marrow mononuclear cell transplantation (BMMCT) improved liver function in decompensated ALD.Design58 patients (mean age 54 yrs; mean MELD score 19, all with cirrhosis, 81% with alcoholic steatohepatitis at baseline liver biopsy) were randomized early after hospital admission to standard medical therapy (SMT) alone (n = 30), including steroids in patients with a Maddrey’s score ≥32, or combined with G-CSF injections and autologous BMMCT into the hepatic artery (n = 28). Bone marrow cells were harvested, isolated and reinfused the same day. The primary endpoint was a ≥3 points decrease in the MELD score at 3 months, corresponding to a clinically relevant improvement in liver function. Liver biopsy was repeated at week 4 to assess changes in Ki67+/CK7+ hepatic progenitor cells (HPC) compartment.ResultsBoth study groups were comparable at baseline. After 3 months, 2 and 4 patients died in the BMMCT and SMT groups, respectively. Adverse events were equally distributed between groups. Moderate alcohol relapse occurred in 31% of patients. The MELD score improved in parallel in both groups during follow-up with 18 patients (64%) from the BMMCT group and 18 patients (53%) from the SMT group reaching the primary endpoint (p = 0.43 (OR 1.6, CI 0.49–5.4) in an intention to treat analysis. Comparing liver biopsy at 4 weeks to baseline, steatosis improved (p<0.001), and proliferating HPC tended to decrease in both groups (−35 and −33%, respectively).ConclusionAutologous BMMCT, compared to SMT is a safe procedure but did not result in an expanded HPC compartment or improved liver function. These data suggest either insufficient regenerative stimulation after BMMCT or resistance to liver regenerative drive in patients with decompensated alcoholic cirrhosis.Trial RegistrationControlled-Trials.com ISRCTN83972743.

Intrathecal Autologous Bone Marrow Mononuclear Cell Transplantation in a Case of Adult Autism

Autism is a complex neurodevelopmental disorder with a worldwide prevalence of 1 in 88. With greater understanding of mechanism of action of cellular therapy it is now possible to address the pathogenesis of autism. Recent findings of cellular therapy offering immunomodulatory, angigogenetic and paracrine effects make it a lucrative option for treatment of autism. We administered a 33 year old adult patient of autism intrathecally, with autologous bone marrow mononuclear cells (BMMNCs), twice with an interval of six months. On follow up at 3, 6 and 9 months post first intervention, he was re-evaluated clinically and no major or minor side effects were observed. At 6 and 9 months objective outcome measures of Indian Scale for Assessment of Autism (ISAA) and Clinical Global Impression (CGI) were used and they showed significant improvement. At the end of 9 months, on ISAA, the score improved from 94 to 64. The CGI showed improvement by change in severity of illness from 3 (Mildly ill) to 1 (Borderline mentally ill). Global improvement on CGI was scored 2 (much improved) with an efficacy index of 5 (moderate therapeutic effect). PET CT scan was repeated at 6 months which showed a balancing effect in the metabolism of affected areas. The changes observed on the PET CT scan correlated with clinical improvements. MRI remained same at 6 months thereby, indicating that PET CT scan may serve as a better monitoring tool for effects of cellular therapy. In this case study, we hypothesize that cellular therapy has repaired the neural connections and achieved balance in the excitatory and inhibitory neuronal cells by various mechanisms of neuroprotection, neuromodulation and neurorestoration. Cell therapy holds great potential and randomized controlled trials may be conducted to study their long term effects in treating autism.

1．脳梗塞患者に対する再生医療の現状とその未来

Cerebral infarction causes permanent neurological damage. Recently, the intravenous administration of bone marrow-derived mononuclear cells has been shown to improve functional recovery through enhanced angiogenesis in an experimental stroke model. Based on these observations, we have started a phase 1/2a clinical trial of cell-based therapy for patients with cardiogenic cerebral embolism. The major inclusion criterion was patients in whom severe cerebral embolism was diagnosed (more than 9 in the NIHSS score on day 7 after the onset of stroke) at age 75 or younger. The patients received 25 ml (low-dose group, n=6) or 50 ml (high-dose group, n=6) of bone marrow aspirate on days 7-10 after the onset of stroke. Autologous bone marrow-derived mononuclear cells were purified by the density gradient method and administered intravenously on the day of cell aspiration. The primary endpoint was safety and improvement of the NIHSS score compared with our historical control. We treated 6 patients in the low-dose group and 4 patients in the high-dose group. No adverse effects were observed and most of the patients showed a significant improvement in neurological function at 6 months after cell transplantation. No enrolled patients showed worsening of the NIHSS score at 30 days after the treatment compared with the NIHSS score before the treatment. Autologous bone marrow mononuclear cell transplantation is apparently safe and feasible, and it improves functional recovery.

Bone-marrow cell therapy induces differentiation of radial glia-like cells and rescues the number of oligodendrocyte progenitors in the subventricular zone after global cerebral ischemia

The subventricular zone (SVZ) is recognized as one of the neurogenic regions in the adult mammalian central nervous system and the presence of cells that share similar characteristics with developmental radial glia, the radial glia-like cells (RGLCs) has been demonstrated in this region. In this study, we investigated whether and how SVZ cells respond to global ischemia and/or to the intravenous transplant of bone-marrow mononuclear cells (BMMCs). Adult rats were subjected to bilateral common carotid ligation (BCCL) and after 1day 2×107 BMMCs or saline injection. The BMMC transplant stimulated a transitory increase in the proliferation of SVZ cells in the BCCL group. We observed a significant increase in the number of RGLCs 3days after ischemia, in both BCCL and BCCL+BMMC groups. However, this increase persisted in the subsequent days only in BCCL animals that received the transplant. BMMC transplantation also inhibits the reduction of NG2-positive oligodendrocyte progenitors in the SVZ observed in the BCCL group. Interestingly, brain-derived neurotrophic factor (BDNF) expression was up-regulated in the SVZ in the treated animals, but not in the other groups. These data thus suggest that BMMC transplantation modulates the phenotype of RGLCs/progenitors in the SVZ and could have a protective role after ischemia.

Bone marrow cell transplantation is associated with fibrogenic cells apoptosis during hepatic regeneration in cholestatic rats

Liver fibrosis is accompanied by hepatocyte death and proliferation of α-SMA(+) fibrogenic cells (activated hepatic stellate cells and myofibroblasts), which synthesize extracellular matrix components that contribute to disorganization of the hepatic parenchyma and loss of liver function. Therefore, apoptosis of these fibrogenic cells is important to hepatic regeneration. This study aimed to analyze the effect of cell therapy using bone marrow mononuclear cell (BMMNC) transplantation on α-SMA expression and on apoptosis of hepatic cells during liver fibrosis induced by bile duct ligation (BDL). Livers were collected from normal rats, fibrotic rats after 14 and 21 days of BDL, and rats that received BMMNC at 14 days of BDL and were analyzed after 7 days. Apoptosis in fibrogenic cells was analyzed by immunoperoxidase, confocal microscopy, and Western blotting, and liver regeneration was assessed by proliferating cell nuclear antigen staining. Results showed that caspase-3 and proliferating cell nuclear antigen expression were significantly increased in the BMMNC-treated group. Additionally, confocal microscopy analysis showed cells coexpressing α-SMA and caspase-3 in these animals, suggesting fibrogenic cell death. These results suggest a novel role for BMMNC in liver regeneration during fibrotic disease by stimulating fibrogenic cells apoptosis and hepatocyte proliferation, probably through secretion of specific cytokines that modulate the hepatic microenvironment toward an antifibrogenic balance.

EFFECT OF AUTOLOGOUS BONE MARROW MONONUCLEAR CELLS TRANSPLANTATION IN DIABETIC PATIENTS WITH ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION

ObjectivesTo investigate the efficacy and proposed mechanism of bone marrow mononuclear cells (BMMNCs) transplantation for diabetic and non-diabetic patients with ST-segment elevation myocardial infarction (STEMI).MethodsOne hundred and sixteen patients with...

Minocycline Treatment and Bone Marrow Mononuclear Cell Transplantation After Endothelin-1 Induced Striatal Ischemia

We explored whether the modulation of microglia activation with minocycline is beneficial to the therapeutic actions of bone marrow mononuclear cells (BMMCs) transplanted after experimental stroke. Male Wistar adult rats were divided in four experimental groups: ischemic control saline treated (G1, N = 6), ischemic minocycline treated (G2, N = 5), ischemic BMMC treated (G3, N = 5), and ischemic minocycline/BMMC treated (G4, N = 6). There was a significant reduction in the number of ED1+ cells in G3 animals (51.31 ± 2.41, P < 0.05), but this effect was more prominent following concomitant treatment with minocycline (G4 = 29.78 ± 1.56). There was conspicuous neuronal preservation in the brains of G4 animals (87.97 ± 4.27) compared with control group (G1 = 47.61 ± 2.25, P < 0.05). The behavioral tests showed better functional recovery in animals of G2, G3, and G4, compared with G1 and baseline (P < 0.05). The results suggest that a proper modulation of microglia activity may contribute to a more permissive ischemic environment contributing to increased neuroprotection and functional recovery following striatal ischemia.

Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms

AbstractTransplantation of whole bone marrow (BMT) as well as ex vivo–expanded mesenchymal stromal cells (MSCs) leads to striking clinical benefits in children with osteogenesis imperfecta (OI); however, the underlying mechanism of these cell therapies has not been elucidated. Here, we show that non–(plastic)–adherent bone marrow cells (NABMCs) are more potent osteoprogenitors than MSCs in mice. Translating these findings to the clinic, a T cell–depleted marrow mononuclear cell boost (> 99.99% NABMC) given to children with OI who had previously undergone BMT resulted in marked growth acceleration in a subset of patients, unambiguously indicating the therapeutic potential of bone marrow cells for these patients. Then, in a murine model of OI, we demonstrated that as the donor NABMCs differentiate to osteoblasts, they contribute normal collagen to the bone matrix. In contrast, MSCs do not substantially engraft in bone, but secrete a soluble mediator that indirectly stimulates growth, data which provide the underlying mechanism of our prior clinical trial of MSC therapy for children with OI. Collectively, our data indicate that both NABMCs and MSCs constitute effective cell therapy for OI, but exert their clinical impact by different, complementary mechanisms. The study is registered at www.clinicaltrials.gov as NCT00187018.

Impact of age on the efficacy of bone marrow mononuclear cell transplantation in experimental stroke

Bone marrow-derived mononuclear cells (BM MNC) have been effectively used to treat experimental stroke. Most of the preclinical trials have been performed in young and healthy laboratory animals, even though age and hypertension are major risk factors for stroke. To determine the influence of age on the properties of BM MNCs after cerebral ischemia, we compared the efficacy of aged and young BM MNC in an in vitro model of cerebral hypoxia and in an adapted in vivo model of stroke. Human BM MNCs were obtained from healthy young or aged donors and either co-cultured with rat hippocampal slices exposed to oxygen glucose deprivation (OGD), or transplanted intravenously 24 h after permanent middle cerebral artery occlusion in aged (18 months) spontaneously hypertensive rats (SHR). Efficacy was examined by quantification of hippocampal cell death, or respectively, by neurofunctional tests and MR investigations. Co-cultivation with young, but not with aged BM MNCs significantly reduced the hippocampal cell death after OGD. Transplantation of both young and old BM MNCs did not reduce functional deficits or ischemic lesion volume after stroke in aged SHR. These results suggest a significant impact of age on the therapeutic efficacy of BM MNCs after cerebral ischemia.

Comparison of Autologous Bone Marrow Mononuclear Cells Transplantation and Mobilization by Granulocyte Colony-Stimulating Factor in Experimental Spinal Injury

ABSTRACTBackground: Recent studies have shown that autologous adult stem cells may be a protocol of treatment for spinal cord injury (SCI) in humans. The purpose of this study was to compare the effect of an injection of autologous bone marrow mononuclear cells (BMMCs) and bone-marrow cell mobilization induced by granulocyte colony stimulating factor (G-CSF) in rats with SCI. Methods: Adult rats were assigned into three groups: control group (SCI only), SCI + BMMCs, and SCI + G − CSF. Neurological scores and electrophysiological testing were done in all rats before SCI, and at 1, 7, 14, 28, 56 days post-SCI. Simultaneously, immunohistochemical labeling and TUNEL assay were performed at the given time. Results: From 1 week post-SCI onward, animals treated with BMMCs or G-CSF had higher BBB scores than control group. Motor and somatosensory evoked potentials (MEPs and SEPs, respectively) of the treated group were significantly better than those in control group at 2 weeks. After sacrifice, compared with the control, animals treated with BMMCs and G-CSF significantly increased expressions of Brdu, NSE, GFAP, Factor VIII, BDNF, and reduced expression of apoptosis cells around the lesion site. Our results indicate that administration of BMMCs and G-CSF in a SCI model achieves similarly positive effect on functional and histologic recovery. Conclusions: The use of G-CSF may be a viable alternative to BMMCs for autograft in patients with SCI.

Bone marrow mononuclear cell transplant therapy in mice with CCl4-induced acute liver failure

Stem cell transplantation has theoretical potential for the treatment of certain liver diseases. However, the use of bone marrow mononuclear cells as a therapy for liver disease has received little attention. The present study was to examine whether bone marrow mononuclear cells might be useful in the management of acute liver failure in an animal model. MATERIALS AND METHOTS: Bone marrow mononuclear cells were harvested from BALB/c mice and then labeled with the fluorescent dye PKH26. The labeled cells were subsequently infused into the tail veins of mice in which hepatic injury had been induced by CCl4 toxicity. After transplantation, the labeled cells in the liver were studied by fluorescent microscopy, and the levels of proliferating cell nuclear antigen and albumin were quantified in bone marrow mononuclear cell-treated and untreated groups. Serum aminotransferase activity was also monitored at various time points post-liver injury. Transplanted bone marrow mononuclear cells labeled with PKH26 were found to populate the damaged liver around the portal and centrolobular regions, and they appeared to differentiate into albumin-producing hepatocyte-like cells. Animals that received bone marrow mononuclear cells also showed a trend toward improved liver enzymes as well enhanced survival rates, relative to controls. These findings suggest that systemically delivered bone marrow mononuclear cells may relocate to and be retained by the injured liver; transplantation of bone marrow mononuclear cells showed an overall beneficial effect in a murine model of acute liver failure.

Intra-Arterial Bone Marrow Mononuclear Cells in Ischemic Stroke

Bone marrow mononuclear cell (BM-MNC) intra-arterial transplantation improves recovery in experimental models of ischemic stroke. We aimed to assess the safety, feasibility, and biological effects of autologous BM-MNC transplantation in patients with stroke. A single-blind (outcomes assessor) controlled Phase I/II trial was conducted in patients with middle cerebral artery stroke. Autologous BM-MNCs were injected intra-arterially between 5 and 9 days after stroke. Follow-up was done for up to 6 months and blood samples were collected for biological markers. The primary outcome was safety and feasibility of the procedure. The secondary outcome was improvement in neurological function. Ten cases (BM-MNC-treated) and 10 control subjects (BM-MNC-nontreated) were consecutively included. Mean National Institutes of Health Stroke Scale before the procedure was 15.6. Mean BM-MNCs injected were 1.59×10(8). There was no death, stroke recurrence, or tumor formation during follow-up, although 2 cases had an isolate partial seizure at 3 months. After transplantation, higher plasma levels of beta nerve growth factor (β-nerve growth factor) were found compared with control subjects (P=0.02). There were no significant differences in neurological function at 180 days. A trend to positive correlation between number of CD34+ cells injected and Barthel Index was found (r=0.56, P=0.09). Intra-arterial BM-MNC transplantation in subacute ischemic stroke is feasible and seems to be safe. Larger randomized trials are needed to confirm the safety and elucidate the efficacy of BM-MNC transplantation. www.clinicaltrials.gov. Unique identifier: NCT00761982.

Plasminogen Activator Inhibitor-1 Controls Bone Marrow-Derived Cells Therapeutic Effect Through MMP9 Signaling: Role in Physiological and Pathological Wound Healing

We assessed the role of plasminogen activator inhibitor-1 (PAI-1) and matrix metalloproteinase 9 (MMP9) in wound healing process and in the bone marrow mononuclear cells (BMMNC)-related effects on physiological and pathological wound healing. A full thickness excision wound was created by removal of the skin on the midback of irradiated and nonirradiated animals. Angiogenesis and re-epithelialization were markedly increased in PAI-1-/- mice compared to wild-type (WT) animals. We revealed high MMP activity in tissue of PAI-1-/- animals. Of interest, the wound healing process was reduced in PAI-1-/-:MMP9-/- animals compared to PAI-1-/- mice, suggesting a key role of MMP9 in beneficial effect of PAI-1 deficiency on wound closure. To unravel the role of PAI-1 in BMMNC relative effects, mice were treated with or without local injection of BMMNC isolated from WT, PAI-1-/-, and PAI-1-/-: MMP9-/- animals for 14 days (10(6) cells, n = 6 per group). In WT nonirradiated mice, transplantation of BMMNC isolated from PAI-1-/- animals enhanced wound formation when compared with WT BMMNC. BMMNC differentiation into cells with endothelial phenotype was enhanced by PAI-1 deficiency. These effects were abrogated in PAI-1-/-:MMP9-/- and MMP9-/- BMMNC. In addition, using chimeric mice, we demonstrated that PAI-1 deficiency environment increased the BMMNC-GFP recruitment to the wound site, whereas this effect was abrogated when using PAI-1-/-:MMP9-/- BMMNC. PAI-1 deficiency, at least through MMP9 upregulation, enhanced wound healing and BMMNC therapeutic potential in irradiated and nonirradiated animals.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Intra-arterial Autologous Bone Marrow Cell Transplantation in a Patient with Upper-extremity Critical Limb Ischemia

Induction of therapeutic angiogenesis by autologous bone marrow mononuclear cell transplantation has been identified as a potential new option in patients with advanced lower-limb ischemia. There is little evidence of the benefit of intra-arterial cell application in upper-limb critical ischemia. We describe a patient with upper-extremity critical limb ischemia with digital gangrene resulting from hypothenar hammer syndrome successfully treated by intra-arterial autologous bone marrow mononuclear cell transplantation.

Modulation of microglial activation enhances neuroprotection and functional recovery derived from bone marrow mononuclear cell transplantation after cortical ischemia

Activated microglia may exacerbate damage in neural disorders; however, it is unknown how they affect stem cells transplanted after stroke. Focal ischemia was induced by microinjections of 40pmol of endothelin-1 into the motor cortex of adult rats. Ischemic animals were treated with sterile saline (n=5), bone marrow mononuclear cells (BMMCs, n=8), minocycline (n=5) or concomitantly with minocycline and BMMCs (n=5). BMMC-treated animals received 5×106BMMCs through the caudal vein 24h post-ischemia. Behavioral tests were performed to evaluate functional recovery. Morphometric and histological analyses were performed to assess infarct area, neuronal loss and microglia/macrophage activation up to 21days post-ischemia. Treatments with minocycline, BMMCs or minocycline-BMMCs reduced infarct area, increased neuronal survival and decreased the number of caspase-3+ and ED-1+ cells, but these effects were more prominent in the minocycline-BMMC group. Behavioral analyses using the modified sticky-tape and open-field tests showed that ischemic rats concomitantly treated with BMMCs and minocycline showed better motor performance than rats treated with BMMCs or minocycline only. The results suggest that proper modulation of the inflammatory response through the blockage of microglia activation enhances neuroprotection and functional recovery induced by intravenous transplantation of BMMCs after motor cortex ischemia.

Intravenous and intra-arterial administration of bone marrow mononuclear cells after focal cerebral ischemia: Is there a difference in biodistribution and efficacy?

Intravascular delivery of cells has been increasingly used in stroke models and clinical trials. We compared the biodistribution and therapeutic effects of bone marrow mononuclear cells (BMMCs) delivered by intra-arterial (IA) or intravenous (IV) injection after cortical ischemia. For the biodistribution analyses, BMMCs were labeled with 99mTechnetium (99mTc). At 2h, gamma-well counting of the brain and of the other organs evaluated did not show differences between the non-ischemic and ischemic groups or between injection routes, and the organs with the highest uptake were the liver and lungs, with low uptake in the brain. At 24h, the liver maintained the highest activity, and a marked decrease was seen in pulmonary uptake in all groups. At this time point, although the activity in the brain remained low, the lesioned hemisphere showed greater homing than the contralateral hemisphere, for both the IV and IA ischemic groups. Histological analysis by CellTrace labeling indicated similar homing between both routes in the peri-infarct region 24h after transplantation and functional recovery was observed in both groups up to 11weeks after the lesion. In conclusion, transplantation of BMMCs by IA or IV routes may lead to similar brain homing and therapeutic efficacy after experimental stroke.