Bone Marrow Mononuclear Stem Cells Research Articles

Dissociation between dopaminergic response and motor behavior following intrastriatal, but not intravenous, transplant of bone marrow mononuclear stem cells in a mouse model of Parkinson’s disease

Parkinson’s disease is characterized by the progressive loss of dopaminergic neurons from the substantia nigra, a process that leads to a dopamine deficiency in the striatum. This deficiency is responsible for the development of motor symptoms, including resting tremor, bradykinesia, rigidity and postural instability. Based on the observation of substantial neuronal death, alternatives to Parkinson’s disease treatment have been studied, including cell-based therapies. The present study aimed to assess the therapeutic potential of intravenous and intrastriatal transplant of bone marrow mononuclear cells in a mouse model of Parkinson’s disease. Animals underwent stereotaxic surgery and received an injection of 6-hydroxydopamine into their medial forebrain bundle. Three weeks later, mice were injected with bone marrow mononuclear cells or saline through the caudal vein or directly into their right striatum. Motor function was assessed using the rotarod and apomorphine-induced rotation tests. Our results showed that intrastriatal bone marrow mononuclear cells, but not intravenous, have a short-term therapeutic effect on dopaminergic response in this mice model of parkinsonism assessed by the apomorphine-induced rotation test. This phenomenon was not identified on the rotarod test, showing dissociation between dopaminergic response and motor behavior. Further experiments are needed to elucidate the precise mechanisms involved in these effects.

FUNCTIONAL AND SYMPTOMATIC IMPROVEMENT AFTER CELLULAR THERAPY IN A PEDIATRIC CASE OF CHRONIC TRAUMATIC INCOMPLETE SPINAL CORD INJURY

Spinal cord injury (SCI) in the pediatric population is a rare incidence and has devastating consequences. Cellular transplantation is one of the emerging strategies in the treatment of SCI. Here, we present a case report of an 8-year-old female who sustained traumatic incomplete SCI at the level of D10-D11 four years ago. Two years after the accident, she underwent 2 doses of cell transplantation with autologous bone marrow mononuclear stem cells (BMMNCs) administered intrathecally (injection into the sub-arachnoid space), followed by intensive neuro- rehabilitation. Over the span of 18 months’ post -cellular therapy, there was improvement in the functional status with FIM (Functional Independence Measure) score improving from 108 to 113. She improved in transfer mobility, static and dynamic balance in sitting and standing positions, ambulation and activities of daily living (ADLs). The bowel and bladder control improvement was significant. There was a shift from A to B on the American Spinal Injury Association (ASIA) scale. Spinal Cord Independence Measure (SCIM) score increased from 73 to 96 after the two cellular therapies. No adverse events related to the transplantation procedure were observed. This case is a “proof of concept study” based on the fact that transplantation of autologous bone marrow mononuclear cells along with rehabilitation may augment the recovery processes in patients with chronic traumatic spinal cord injuries. Further, randomized controlled clinical studies are warranted to prove it’s the therapeutic efficiency.

Intra-arterial Infusion of Autologous Bone Marrow Mononuclear Stem Cells in Subacute Ischemic Stroke Patients.

Based on many preclinical and small clinical trials, stem cells can help stroke patient with the possibility of replacing the cells and supporting the remaining cells. The aim of this study was to evaluate the safety and feasibility of bone marrow mononuclear (BMMN) stem cell transplantation in subacute ischemic stroke patients. Thirty-nine (n = 39) patients with subacute ischemic cerebral infarct due to large artery occlusion in the middle cerebral artery (MCA) territory were recruited. They were distributed into two groups: first group (n = 21) served as an experimental group, which received intra-arterial (IA) mononuclear stem cells (bone marrow-derived mononuclear cell), while the other group (n = 18) served as a control group. All the patients were evaluated clinically by National Institutes of Health Stroke Scale, modified Rankin Scale, Barthel Index, modified and standardized Arabic version of the Comprehensive Aphasia Test, and radiological for 12 months. The stem cell-treated group showed better improvement, but it was not significant when compared with the non-treated group. The volume of infarction changes at the end of the study was non-significant between both the groups. There was no, or minimal, adverse reactions in stem cell-treated group. The study results suggest that autologous BMMN stem cell IA transplantation in subacute MCA ischemic stroke patients is safe with very minimal hazards, but no significant improvement of motor, language disturbance, or infarction volume was detected in stem cell-treated group compared with the non-treated group.

Autologous Bone Marrow Derived Stem Cells for the Treatment of Multiple Sclerosis.

Stem cell therapy, an evolving, progressive field of therapeutics has shown several successes in areas where classic treatments failed to prevent or stop disability. Starting in 2009, twenty two sequential patients with progressive Multiple Sclerosis (MS) courses were treated with Autologous Bone Marrow Mononuclear stem cells (BM-MNSCs). The cells were given both intravenously and intrathecally. Using the Expanded Disability Status Scale (EDSS) score for evaluation, our data indicates that the majority of the patients benefited on the average one point on the scale. This paper adds to the body of evidence suggesting the safety and efficacy of autologous BM-MNSCs in the treatment of MS and awaits validation through larger, randomized studies.

Intrabone marrow injection enhances placental mesenchymal stem cellmediated support of hematopoiesis in mice.

In order to determine the synergistic effects of human placental mesenchymal stem cells (PMSCs) on hematopoiesis in vivo, we compared the intrabone marrow injection (IBMI) with the conventional intravenous injection (IVI). C57BL/6 recipient mice conditioned with lethal doses of irradiation were transplanted with bone marrow mononuclear cells (MNCs) and bone marrow-derived mesenchymal stem cells (BMSCs) from BALB/c mice by IBMI or IVI. NOD/SCID recipient mice conditioned with sublethal doses of irradiation were transplanted with human umbilical cord blood MNCs (UCB-MNCs) and PMSCs by IBMI or IVI. The number of hematopoietic cells was significantly higher in mice transplanted with BMSCs by IBMI than in those transplanted by IVI in a murine transplantation model (BALB/c→C57BL/6). Moreover, the percentage of human hematopoietic cells in the tibiae of the NOD/SCID mice that were transplanted with PMSCs plus UCB-MNCs was higher than that in mice transplanted with UCB-MNCs alone. In addition, in mice that were transplanted with PMSCs, PMSCs injected by IBMI were more efficient than those injected by IVI. Our results not only elucidated the role of PMSCs in promoting hematopoiesis, but also revealed the therapeutic potential of the combination of PMSCs and IBMI in transplantation.

Bone Marrow-Derived Cells as a Therapeutic Approach to Optic Nerve Diseases.

Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs) of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized.

Cardiac stem cell therapies for congenital heart diseases

During the last 2 decades, stem cell therapies with bone marrow mononuclear cells (BMMNCs) or mesenchymal stem cells (MSCs) to treat ischemic heart disease, including in pre-clinical and clinical trials, have demonstrated the ability of stem cells to improve cardiac function, infarct size, and cardiac remodeling in adult patients. In recent years, endogenous cardiac stem cells (CSCs) derived from heart tissue have been identified. CSCs have been shown to have superior regenerative potential over other types of stem cells in terms of cardiovascular-lineage differentiation, paracrine factor secretion, and functional improvement after cell transplantation. Cardiac stem cell therapy to regenerate damaged myocardium after chronic infarction has been reported in the SCIPIO and CADUCEUS trials. In contrast, although recent advances in pediatric cardiology, congenital cardiac surgery, and intensive care management have dramatically changed clinical outcomes, there is an increasing recognition of limited therapeutic improvement in children with severe heart failure. Congenital heart failure is a structural heart disease caused by multiple etiologies related to pressure and volume overload, arrhythmia, and myocardial degradation. Stem cell-based strategies to treat heart failure in adults have been investigated; however, little is known about their safety and efficacy in children and planned clinical studies are quite limited. Only case reports have been published and no large clinical trials have been conducted using any type of stem cells. Recently, the TICAP trial has revealed the safety and feasibility of intracoronary infusion of autologous cardiosphere-derived cells (CDCs) in children with hypoplastic left heart syndrome (HLHS). Although this trial had several limitations that required further evaluation, the results from this study provided a foothold for stem cell-based therapeutic strategies in patients with congenital heart disease. Eventually, a new paradigm of stem cell therapy to treat congenital heart failure has started to form. Many important issues including long-term cell engraftment, the mechanism of stem cell recruitment and differentiation, administration route, and appropriate cell types to deliver in situ remain to be investigated. Here, we review the latest research on stem cell therapies for heart failure and discuss the future perspectives on cell-based regenerative strategies to treat patients with congenital heart diseases.

Attenuation of Hindlimb Ischemia after Associated Autologous Transplantation of Bone Marrow Mononuclear Cells and Platelet Rich Plasma

Objective: The purpose of this study was to determine whether autologous bone marrow mononuclear stem cell (BMCs) associated with platelet rich plasma (PRP) transplantation improves peripheral collateralization in a rabbit ischemic limb model. Methods: Unilateral hindlimb ischemia was surgically induced in New Zealand White rabbits (n=30). A total of 106 BMCs+PRP were intramuscularly implanted into each ischemic limb. Blood flow was monitored by Doppler in the ischemic and control animals. Histological analysis of capillary density in the ischemic limbs was performed 30 days after the ischemia induction. Results: Histological sections of ischemic gastrocnemius muscle showed that capillary index (capillary/muscle fiber) was greater in the BMCs+PRP implantation group 30 days after the ischemia induction than in the saline group. Conclusion: This study demonstrated that implantation of BMCs+PRP into ischemic limbs effectively induces collateral vessel formation, suggesting that this cell therapy is useful as a novel strategy for therapeutic peripheral arterial disease.

Stem cells for the treatment of cardiovascular diseases. An update

Available medical therapy is unable to completely prevent or revert the pathological cardiac remodeling secondary to ischemia or other injuries, which is responsible for the development of heart failure. Regenerative medicine through stem cells had an explosive development in the cardiovascular area during the past decade. Stem cells possess the capacity to regenerate, repair or substitute damaged tissue, allowing the reestablishment of its function. Stem cells can also modulate apoptosis, angiogenesis, fibrosis and inflammation, favoring the endogenous regenerative process initiated by the damaged tissue. These capacities have been corroborated in several animal models of cardiovascular diseases with positive results. In humans, therapies with bone marrow mononuclear stem cells, mesenchymal stem cells and cardiac stem cells are safe. Most randomized clinical trials in patients with myocardial infarction or cardiomyopathies of different etiologies have reported benefits on ventricular function, quality of life and even over mortality of treated patients. This article reviews the state of art of stem cell therapy in cardiovascular diseases, focusing on the most common cellular types used in patients with acute myocardial infarction and chronic cardiomyopathies of different etiologies.

Abstract 143: Evaluation of the Paracrine Effect of Encapsulated Mononuclear Stem Cells in the Acute Myocardial Rat Model

Many studies have considered stem cell-based therapy as a treatment option for acute myocardial infarction (AMI). Paracrine signaling has been proposed as an underlying mechanism, in which released cytokines and chemokines may promote angiogenesis and activation of resident stem cells. In order to characterize this paracrine action, bone marrow mononuclear stem cells (BM-MNC) collected from femur of adults GFP+ Wistar rats were encapsulated in 1.5% of sodium alginate. Animals were randomized in three groups: SHAM (n=3); Empty capsules (n=8); BM-MNC capsules (n=8). AMI was induced by permanent occlusion of the left anterior descending artery after anesthesia with 100mg/kg ketamin and 10 mg/kg xylazine. Soon after the AMI, capsules (empty or BM-MNC) were delivered intra-thoracically. SHAM group was submitted to the same surgical procedures without permanent artery occlusion or treatment given. Troponin I (cTnI) was measured 24h after AMI in order to evaluate the success of the procedures; echocardiography was also performed to assess heart morphofunctional parameters 48h and 7 days after AMI. At day 7, after echocardiography, the animals were euthanized under profound anesthesia (isoflurane 5%) and their hearts were withdrawn for biochemical analysis. Plasma and tissue levels of TNF-α and IL-6 were measured by ELISA. All technical procedures were performed by blinded operators. Statistical comparisons were made using ANOVA analysis followed by Tukey post-test or using t-Student test when appropriated. BM-MNC were viable after day 7 since GFP+ cells were detected by fluorescence microscopy. Nevertheless, the empty capsules groups showed lower levels cTnI compared to BM-MNC group (25 vs. 40 ng/mL, respectively; p=0.03). There was no difference in the shortening fraction (24% VS. 18%, respectively; p=0.08) and in the infarcted area (32% vs. 43%, respectively; p=0.10) when both AMI groups (Empty and BM-MNC) were compared. Also TNF-α and IL-6 levels showed no difference between all groups. We concluded that paracrine effects of cell-based therapy with BM-MNC was unable to modulate events associated to AMI in rat in spite of cell viability after 7 days of implantation.

Flap Prefabrication and Stem Cell–Assisted Tissue Expansion

Total face skin and soft-tissue defects remain one of the biggest challenges in reconstructive surgery. Reconstruction of the entire face with uniform coverage and delicate features is difficult to achieve. To avoid the patchwork result seen in multiple flaps and skin grafts, 1 monoblock flap that has similar color, texture, and thickness might be an ideal option to minimize the incisional scars and several surgical procedures but is unavailable with current approaches because of the lack of sufficient matched tissue and the unreliable blood supply for such a large flap. To acquire a monoblock flap for full face reconstruction, we combine the prefabricated flaps, skin overexpansion, and bone marrow mononuclear stem cell transplantation for total facial resurfacing. In this article, we present our experience from our case series that provides universally matched skin and near-normal facial contour. It is a reliable and an excellent reconstructive option for massive facial skin defect.

In vivo Bioluminescence Imaging Monitoring of Stem Cells' Participation in Choroidal Neovascularization

Background: Choroidal neovascularization (CNV) is common in various retinal diseases and is one of the most common causes of severe and irreversible visual loss. Our previous works suggested that bone marrow-derived cells (BMCs) participate in CNV, but little is known about stem cells' dynamic change when injected into mouse CNV. In vivo optical bioluminescence imaging (BLI) is a newly developing technology for dynamically observing biological behavior. Using this technology, we can observe the stem cells' dynamic behavior in CNV, in vivo. Methods: Two types of BMCs were used: bone marrow mononuclear cells (BMMNCs) and bone mesenchymal stem cells (MSCs). Cells were characterized using flow cytometry and BLI. C57BL/6J mice (n = 6/group) underwent CNV followed by caudal vein injection of 4 × 10⁶ BMMNCs, MSCs or phosphate buffer. Cell survival was measured: (1) in vivo using BLI during 2 weeks, and (2) in vitro using firefly luciferase (Fluc) assays and histology. Results: BMMNCs and MSCs expressed a similar Fluc reporter enzyme, as confirmed by luminometry. After injection into CNV mouse models, the two cell types showed dynamic behavior in CNV using BLI. The in vitro Fluc assay and histology results provided further proof for the above results. Conclusion: This is the first study comparing the behavior of stem cells in CNV using BLI, in vivo. BMMNCs and MSCs could contribute to CNV and could serve as delivery vehicles for CNV treatments. Meanwhile, BLI could lay a foundation for CNV mechanism research in a prospective manner.

Abstract 19135: Safety and Efficacy of Intramyocardial Delivery of Stem Cells in Ischemic Heart Failure: An Individual Patient Data-Based Meta-Analysis

Background. Intramyocardial stem cell delivery mode might be the choice for regeneration of chronic myocardial ischemia and/or left ventricular (LV) dysfunction. Methods. Individual patient data-based meta-analysis includes data of 383 patients (part of MESS database, clinicaltrials.gov NCT01098591 ) with ischemic cardiomyopathy (iCMP) and treated either with autologous stem cell (SC) (bone marrow mononuclear or mesenchymal stem cells) using percutaneous 3D NOGA-guided delivery (n=290) or randomized to controls (n=93), data received from 5 European centers. Results. The average follow-up (FUP) was 6.4±2.2 months. The baseline end-diastolic volume (189±73 ml vs 201±71 ml) and ejection fraction (EF) (41.4±14.5% vs 42.5±18.7%) were similar in SC treated vs controls. Procedural complication occurred in 2.1% of patients, and 80.8x10^6 cells were delivered in 11.2±2.5 myocardial sites. Compared with controls, intramyocardial delivery of SC improved (p<0.001) LV EF (mean difference 4.6%; 95% confidence interval /CI/ 6.4% to 2.7%); reduced infarct size (-2.22%; 95% CI -3.54% to -0.90%) and size of stress-induced myocardial ischemia (-5.6; 95% CI -7.38% to -3.88%). The CCS angina status (-1.0; 95% CI -0.68 to -1.06) and NYHA (-0.74; 95% CI -0.54 to -0.93) improved significantly (p<0.001) post SC therapy as compared with controls. Kaplan-Meier analysis resulted in a significant better survival (98.8% vs 93.5%, p<0.01) and MACCE-free survival (97.9% vs 78.5%, p<0.001) rate in SC-treated patients vs controls. Multivariate analysis resulted in a lower baseline EF and higher total number of intramyocardial delivered SC as significant predictors for improvement in EF, while norminal regression analysis revealed SC therapy as significant predictor for MACCE-free survival in patients with iCMP. Conclusion. Meta-analysis of 3D NOGA endocardial mapping guided transendocardial stem cell treatment proves the safety and efficacy of this cardiac regeneration strategy in patients with chronic ischemia and low EF.

Safety Profile of Bone Marrow Mononuclear Stem Cells in the Rehabilitation of Patients with Posttraumatic Facial Nerve Paralysis—A Novel Modality (Phase One Trial)

Objectives The objectives of this study were to study the safety profile and role of mononuclear stem cells in the rehabilitation of posttraumatic facial nerve paralysis not improving with conventional treatment. Study Design This is a prospective nonrandomized controlled trial. Study Setting This study is conducted at Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh between July, 2007 and December, 2008. Patients We included eight patients of either sex aged between 18 and 60 years of posttraumatic facial nerve paralysis not improving with conventional treatment presented to PGIMER, Chandigarh between July 2007 and December 2008. Methods All patients underwent preoperative electroneuronography (ENoG), clinical photography, and high-resolution computed tomography (HRCT) temporal bone. All patients then underwent facial nerve decompression and stem cell implantation. Stem cells processing was done in well-equipped bone marrow laboratory. Postoperatively, all patients underwent repeat ENoG and clinical photography at 3 and 6 months to assess for objective and clinical improvement. Clinical improvement was graded according to modified House-Brackmann grading system. Intervention Done All patients of posttraumatic facial nerve paralysis who were not improving with conventional surgical treatment were subjected to facial nerve decompression and stem cell implantation. Main Outcome Measures All patients who were subjected to stem cell implantation were followed up for 6 months to assess for any adverse effects of stem cell therapy on human beings; no adverse effects were seen in any of our patients after more than 6 months of follow-up. Results Majority of the patients were male, with motor vehicle accidents as the most common cause of injury in our series. Majority had longitudinal fractures on HRCT temporal bone. The significant improvement in ENoG amplitude was seen between preoperative and postoperative amplitudes on involved side which was statistically significant (0.041). Clinical improvement seen was statistically significant both for eye closure (p < 0.010) and for deviation of angle of mouth (p < 0.008) at 6-month follow-up in 85% of our patients, far better than the results of previous conventional surgeries. Conclusion Stem cell therapy can be used safely in human beings without any adverse effects on humans, and it appears to be a promising modality for rehabilitation of patients with posttraumatic facial nerve paralysis not improving with conventional surgical treatment but few more clinical series are required for validation.

Stem Cell Therapy in Spinal Cord Injury: In Vivo and Postmortem Tracking of Bone Marrow Mononuclear or Mesenchymal Stem Cells

The aim of this study was to address the question of whether bone marrow-originated mononuclear cells (MNC) or mesenchymal stem cells (MSC) induce neural regeneration when implanted intraspinally. The study design included 4 groups of mice: Group 1, non-traumatized control group; Groups 2, 3 and 4 spinal cord traumatized mice with 1 g force Tator clips, which received intralesionally either no cellular implants (Group 2), luciferase (Luc) (+) MNC (Group 3) or MSC (Group 4) obtained from CMV-Luc or beta-actin Luc donor transgenic mice. Following the surgery until decapitation, periodical radioluminescence imaging (RLI) and Basso Mouse Scale (BMS) evaluations was performed to monitor neural activity. Postmortem immunohistochemical techniques were used to analyze the fate of donor type implanted cells. All mice of Groups 3 and 4 showed various degrees of improvement in the BMS scores, whereas there was no change in Groups 1 and 2. The functional improvement was significantly better in Group 4 compared to Group 3 (18 vs 8, p=0.002). The immunohistochemical staining demonstrated GFP(+)Luc(+) neuronal/glial cells that were also positive with one or more of these markers: nestin, myelin associated glycoprotein, microtubule associated protein or myelin oligodendrocyte specific protein, which is considered as indicator of donor type neuronal regeneration. Frequency of donor type neuronal cells; Luc + signals and median BMS scores were observed 48-64% and 68-72%; 44-80%; 8 and 18 within Groups III and IV respectively. MSCs were more effective than MNC in obtaining neuronal recovery. Substantial but incomplete functional improvement was associated with donor type in vivo imaging signals more frequently than the number of neuronal cells expressing donor markers in spinal cord sections in vitro. Our results are in favor of functional recovery arising from both donor MSC and MNCs, contributing to direct neuronal regeneration and additional indirect mechanisms.

Autotransplantation of immobilized stromal bone marrow cells during lumbar spondylosyndesis in an experiment

Aim. To assess the ability of immobilized autologous bone marrow stromal cells to provide an effective repair with the formation of a robust bone block in the area of the interbody defect of the spinal motor segment after total removal of the intervertebral disc. Methods. Studied were the effects of autotransplantation of different cell fractions isolated from the bone marrow (mononuclear, stromal cells and stromal stem cells) on the formation of the anterior bone block during interbody spondylosyndesis in an experiment on 24 mongrel dogs of different sexes (mean weight 18.3 kg, the mean diameter of the lumbar vertebral bodies according to radiographic study 18.6 mm). All animals underwent the crest puncture the right wing of the ilium, with aspiration of 10 ml of bone marrow, conducted was a total diskectomy at the level of the bodies of the VII and VIII lumbar vertebras with replacement of the interbody defect with a porous metal cylinder of the Nickel titanium of an appropriate shape and size. All animals were randomly divided into four groups, 6 in each. In the first group the interbody defect was filled with a porous metal cylinder only, in the second group - with the fraction of bone marrow mononuclear cells, in the third - with the fraction of stromal cells, in the fourth - with the fraction of culture-grown stromal cells. Results. In the first (control) group established were the signs of delayed formation of the anterior bone block, formation of the hypertrophic interbody pseudarthrosis. Noted was the formation of coarse fibrous capsule in the zone of «implant-bone» contact, an excess of cartilage tissue, the small size and low proliferative activity of osteoblasts, hypoplasia of the blood vessels. In the second group determined was the forming artificial bone block with paravertebral hyperostosis, radiologically - microdislocation of the implant with protrusion into the body of the adjacent vertebra and partial osteointegration with the porous structure of the fixer in the contact «implant-bone» zone. Bone formation occurred by the type of secondary osteogenesis with an excess of cartilage tissue. In the third and fourth groups formed was a robust artificial bone block, no signs of implant dislocation were observed. Determined was the full osteointegration of the porous structure of the fixer in the contact «implant-bone» zone. The newly formed bone tissue surrounded the implant in a muft-like fashion and grew into its porous structure, grew into the periosteal zone of adjacent vertebral bodies, well adhering with their surface. Conclusion. The proposed method of correction of osteoreparation disorders can be considered as an alternative to osteoplastic operations with the transplantation of massive bone grafts, as well as in conditions of systemic disorders of the ostepoetic function with a critical shortage of endogenous progenitors of bone cells.

Bone Marrow Mononuclear Stem Cell Transplant in Acute and Chronic Arterial Insufficiency in Rabbits

Introduction: There is a high incidence of Peripheral Obstructive Arterial Disease (POAD) in patients with atherosclerosis. In more complex cases for which surgical revascularization is not possible, the only option involves clinical treatment that in the majority of cases evolves to amputation of the limb. Transplant of mononuclear stem cells from bone marrow has presented favorable results in chronic obstructions. Objective: To perform a functional analysis of the effect of bone marrow mononuclear stem cell transplant on acute arterial occlusion immediately and 48 hours after occlusion, comparing between groups and with controls. Materials and methods: Twenty New Zealand rabbits were anesthetized with ketamine and xylazine (50 mg/ kg) and underwent occlusion of the right iliac artery. Those animals that presented absence of arterial flow after ligation were included in the study. These animals were then randomized and divided into four groups: Group 1(n=5) control of acute ischemia group–injection of saline solution, Group 2(n=5) control of chronic ischemia–injection of saline solution 48hrs after occlusion. Group 3(n=5) transplant of stem cell in acute ischemia group, and Group 4(n=5) transplant of stem cells in the chronic ischemia group, 48hrs after occlusion. The animals were evaluated by the Tarlov’s movement scale, degree of tissue ischemia, and degree of modified ischemia on the seventh, fourteenth and thirtieth day after arterial occlusion. This evaluation was performed in a blind and randomized fashion by two different observers. The animals underwent another vascular Doppler exam on the thirtieth day after arterial occlusion. Results: All animals were considered homogeneous in the pre-transplant period. No statistical differences were identified between groups G1 and G3 (p=109) with respect to Tarlov scale. Regarding the intergroup analysis, a clinical improvement was observed in Group 4 when compared to Groups 1, 2, and 3, p=0.003, p=0.0025, and p=0.055 respectively, on the thirtieth day after occlusion. No significant difference was observed for the degree of ischemia and modified ischemia parameters after transplant. Conclusion: Clinical improvement in the chronic ischemia group receiving cell transplant of mononuclear stem cells was observed in comparison to the control group and in relationship to the acute ischemia group, suggesting a functional improvement in the affected limb.

Treatment with Autologous Bone Marrow Mononuclear Cells in Patients with Non Reconstructable Critical Lower Limb Ischaemia

Background and Aims: Treatment with autologous, bone marrow mononuclear stem cells has shown effects in patients with chronic limb ischaemia. The aim of the study was to test the potential effect of stem cell treatment in a strict defined group of patients with non reconstructable critical limb ischaemia (CLI). Material: Twenty patients with non recontructable CLI of the lower extremities, who received medical treatment in the form of prostavasine. Methods: Bone marrow cells were harvested from the patient’s iliac crest and, after separation, injected into the calf muscles of the affected leg. Outcome was evaluated by digital subtraction angiography (DSA), visual analogue scale (VAO) one patient was amputated two months after cell injection. Two patients reported relief of pain after four months. Conclusion: This method seems to be a safe option for treating patients with non reconstructable CLI.

Is the measurement of left ventricular ejection fraction the proper end point for cell therapy trials? An analysis of the effect of bone marrow mononuclear stem cell administration on left ventricular ejection fraction after ST-segment elevation myocardial infarction when evaluated by cardiac magnetic resonance imaging

The measurement of left ventricular (LV) ejection fraction (LVEF) is a strong predictor of cardiovascular adverse events and mortality in patients with LV dysfunction and has become the most common primary end point in cardiovascular cell therapy trials after ST-segment elevation myocardial infarction (STEMI). Multiple small trials have been performed using bone marrow mononuclear stem cells (BMCs) in this setting with several meta-analyses demonstrating that BMC administration results in a small improvement in LVEF and may attenuate adverse LV remodeling. However, individual trial results have not been uniform, and the measurement of LVEF in these trials has relied on a variety of imaging techniques including LV angiograpnhy, single-photon emission computed tomography, echocardiography, or cardiac magnetic resonance imaging (cMRI). Because cMRI provides the most accurate measurement of LVEF, LV volumes, and infarct size in patients after STEMI, we reviewed all randomized cardiovascular stem cell trials (N = 10) that administered intracoronary BMCs versus placebo/control to 686 patients after primary percutaneous coronary intervention treatment of STEMI that used cMRI as their principal imaging measurement of LVEF at baseline and 3 to 6 months later. Administration of BMCs was associated with a nonsignificant 0.9% ± 0.8% absolute increase in LVEF compared with placebo or control (95% CI -0.7 to 2.4) with a small but nonsignificant decrease LV end-diastolic and LV end-systolic volumes (LV end-diastolic volume -1.1 ± 1.5 mL/m(2), LV end-systolic volume -1.6 ± 1.4 mL/m(2)). Although infarct size uniformly decreased over time, the reduction was not improved by BMC administration (-0.3 ± 1.7 g). The benefit of BMC administration after STEMI on LVEF, LV volumes, and infarct size is small when assessed by cMRI.

Hybrid approach of ventricular assist device and autologous bone marrow stem cells implantation in end-stage ischemic heart failure enhances myocardial reperfusion

We challenge the hypothesis of enhanced myocardial reperfusion after implanting a left ventricular assist device together with bone marrow mononuclear stem cells in patients with end-stage ischemic cardiomyopathy. Irreversible myocardial loss observed in ischemic cardiomyopathy leads to progressive cardiac remodelling and dysfunction through a complex neurohormonal cascade. New generation assist devices promote myocardial recovery only in patients with dilated or peripartum cardiomyopathy. In the setting of diffuse myocardial ischemia not amenable to revascularization, native myocardial recovery has not been observed after implantation of an assist device as destination therapy. The hybrid approach of implanting autologous bone marrow stem cells during assist device implantation may eventually improve native cardiac function, which may be associated with a better prognosis eventually ameliorating the need for subsequent heart transplantation. The aforementioned hypothesis has to be tested with well-designed prospective multicentre studies.