Bone Marrow Stem Cell Therapy Research Articles

The Efficacy of Bone Marrow Stem Cell Therapy in Hip Osteoarthritis: A Scoping Review

Background: Hip osteoarthritis (HOA) is a prevalent degenerative joint disease with various treatment approaches. Biological agents, such as bone-marrow derived stem cells (BM-MSC) therapy, have recently been proposed as a treatment option in the management of HOA. Purpose: We sought to further analyze the use of BM-MSC therapy by investigating the following questions. What is the standard preparation and practice? Does a dose response exist between stem cell therapy and clinical outcome? Does BM-MSC therapy alone produce effective clinical outcomes? Methods: We conducted a scoping review using the Methodological Expectations of Cochrane Intervention Reviews Manual and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines for scoping reviews. A comprehensive search of PubMed, Embase, Cochrane CENTRAL, Scopus, SPORTDiscus, Cumulative Index to Nursing and Allied Health Literature, and Web of Science Core Collection was performed in June 2023 of studies using exclusively BM-MSC injections for the treatment of HOA. Study characteristic, injection preparation and dosage, clinical outcome measures, and adverse effect data were extracted and interpreted by 3 reviewers. Results: Seven studies with a total of 72 patients met the inclusion criteria. Clinical outcome following intra-articular injection of BM-MSCs was measured using the numerical pain scale, the Western Ontario and McMaster Universities Osteoarthritis Index, the visual analogue scale, and other scores, all of which showed reduction in pain and increase in functional ability across studies. Conclusions: This scoping review found that the efficacy of BM-MSC therapy alone in the treatment of HOA appeared beneficial, improving clinical outcomes in each study. All 7 studies used “low-dose” injections with variable follow-up times; thus, a clear dose–response relationship cannot be drawn. Future studies using high doses and analyzing long-term effects of BM-MSC injections in HOA are needed.

Clinical Outcomes by Consolidation of Bone Marrow Stem Cell Therapy and Coronary Artery Bypass Graft in Patients With Heart Failure With Reduced Ejection Fraction: A Meta-analysis

Bone marrow stem cell (BMSC) transplantation during coronary artery bypass graft (CABG) is an innovative treatment for ischemic heart disease (IHD). We conduct a meta-analysis to examine whether patients with IHD presenting heart failure with reduced ejection fraction (HFrEF) can be beneficent from CABG with additional BMSC transplantation. Electronic searches were performed on PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov from their inception to July 2021. The efficacy was based on left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic volume index (LVEDVi), left ventricular end-systolic volume index (LVESVi), and 6-min walk test (6MWT) change after treatment. Eight randomized-controlled trials (RCTs) were included in this meta-analysis, with a total of 350 patients. Results showed BMSC transplantation significantly improved the LVEF [mean difference (MD) = 6.23%, 95% confidence interval (CI): 3.22%–9.24%, P < 0.0001], LVEDVi (MD = −20.15 ml/m2, 95% CI: −30.49 to −9.82 ml/m2, P < 0.00001), and LVESVi (MD = −17.69 ml/m2, 95% CI: −25.24 to −10.14 ml/m2, P < 0.00001). There was no statistically significant difference in the improvement of LVEDD, LVEDV, and 6MWT between the cell transplantation group and control groups. Subgroup analysis revealed that the intervention for control group could affect the efficacy of BMSC transplantation. Sensitivity analysis found the conclusion of LVEDD, LVEDV, and 6MWT changes was not stable. Therefore, among patients with IHD presenting HFrEF, BMSC transplantation during CABG is promising to be beneficial for postoperative left ventricular (LV) function improvement. However, according to the unstable results of the sensitivity analysis, it cannot be concluded whether the extra step has a positive effect on left ventricular remodeling and exercise capacity. RCTs with larger cohorts and more strict protocols are needed to validate these conclusions.

Factors Affecting Outcomes of Bone Marrow Stem Cell Therapy for Acute Myocardial Infarction

Myocardial infarction (MI) poses a significant burden to both patients and the health care system. The irreversible loss of functional cardiomyocytes due to ischemia threatens both patients’ immediate survival and quality of life over their lifespan. Stem cell therapy has been proposed as a solution to salvage cardiac contractility through the regeneration of cardiomyocytes, and bone marrow–derived stem cells (BMSc) are among the category of stem cells most extensively studied. Despite the promising theoretical potential of BMSc in tissue regeneration, several key aspects remain to be better understood to enable large-scale clinical application, including safety and efficacy. Our current work in synthesizing and evaluating both preclinical and clinical studies using stem cell applications in acute MI has demonstrated that BMSc transplantation is a safe therapy for MI. Although this therapy’s efficacy is not consistently proven, we have significantly improved our understanding of factors contributing to its success, such as the stem cell type, patients’ baseline left ventricular ejection fraction, individual hemodynamic factors, and differential expressions of specific genes. In future investigations, researchers should focus on the cellular and individual attributes of BMSc treatment to achieve maximal efficacy and outcomes for patients receiving this therapy after acute MI.

Subcutaneous osteochondral regeneration using a bilayer scaffold by leveraging angiogenic activities

• A gelatin-based bilayer scaffold with Cur/GT as upper and DS/GT as bottom layer was developed. • Cur/GT exerted antiangiogenic activity to the stable chondrogenesis of BMSCs. • DS/GT endowed proangiogenic effects to promote osteogenesis of BMSCs. • The BMSC-loaded bilayer scaffold achieved subcutaneous osteochondral regeneration. Bone marrow stem cell (BMSC) therapy is a promising method to achieve subcutaneous osteochondral regeneration. However, it remains obscure due to the incorrect angiogenic niche. Studies have demonstrated that an antiangiogenic niche promotes cartilage regeneration, whereas a proangiogenic niche facilitates bone formation. Considering that curcumin (Cur) is an antiangiogenic drug and Danshen (DS) is a proangiogenic drug, this study is the first to develop a gelatin-based bilayer porous scaffold, where curcumin-loaded gelatin (Cur/GT) was used as the upper layer and DanShen-loaded gelatin (DS/GT) was used as the bottom layer. The data revealed that both Cur and DS could be sustained and released from Cur/GT and DS/GT, respectively. When cocultured with human umbilical vein endothelial cells, Cur/GT inhibited tube formation, whereas DS/GT promoted tube formation. Furthermore, the findings demonstrated that the Cur addition in the upper layer exerted antiangiogenic activity to the stable chondrogenesis of BMSCs, the DS addition in the bottom layer endowed proangiogenic effects to promote osteogenesis of BMSCs, and the bilayer scaffold successfully achieved subcutaneous osteochondral regeneration when recolonized with BMSCs. This study provides new insight into subcutaneous osteochondral regeneration by leveraging the angiogenic microenvironment.

Major clinical findings of cellular therapy for intravitreal use in ischemic retinopathy and macular degeneration: a systematic review

Introduction: In the scenario of eye diseases, diabetic retinopathy and retinal vein occlusion are the two most common ischemic retinopathies in the world. Ischemia is caused by retinal vascular diseases due to decreased blood perfusion and the appearance of areas of retinal non-perfusion. Also, age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in people over 65 years of age in industrialized countries. By 2020, around 200 million people will be affected by AMD worldwide. Objective: the present systematic review study aimed to highlight the main clinical findings of the treatment of ischemic retinopathy and age-related macular degeneration through cell therapy with bone marrow stem cells. Methods: The rules of the Systematic Review-PRISMA Platform were followed. The search was carried out from March 2022 to June 2022 in Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument. The risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: It was found 235 articles involving retinitis pigmentosa, macular degeneration, and bone marrow stem cell therapy. A total of 51 were fully evaluated and 28 studies were included and developed in a systematic review in the results field. The symmetrical Funnel Plot does not suggest a risk of bias between the small sample size studies. It was concluded that intravitreal injection of bone marrow-derived stem cells in a patient with retinal vascular occlusion sequelae demonstrated that the procedure is feasible and safe to be performed in humans as there were no signs of infection, inflammation, or development of intraocular tumor formation. Also, neurotrophic effects correlate with vasculature preservation, suggesting that bone marrow-derived stem cells can be used in the treatment of diseases such as retinal degenerations and vasculopathy that currently lack effective treatment. The authors concluded that stem cells can protect retinal cells from degeneration and also suggested that they were able to replace some types of lost retinal neurons.

Influence of Autologous Bone Marrow Stem Cell Therapy on the Levels of Inflammatory Factors and Conexin43 of Patients with Moyamoya Disease.

Moyamoya disease is a medical condition that shows the typical characteristics like continuous and chronic thickening of the walls and the contraction of the internal carotid artery; as a result, the internal diameter of the artery gets narrowed. There are six phases of the disease ranging from I to VI (moyamoya vessels completely disappear, followed by the complete blockage of the arteries). Surgery is a commonly recommended treatment for the moyamoya disease. Our research study identifies the effect of autologous bone marrow stem cell therapy (ABMSCT) on the levels of inflammatory factors and Conexin43 (Cx43) protein in patients suffering from moyamoya. In our study, we have selected 52 moyamoya patients admitted to our hospital from 30 July 2019 to 10 February 2020. The control group (CG) was treated with superficial temporal artery to a middle cerebral artery (STA-MCA) bypass + encephalo-duro-myosinangiosis (EDMS). The experimental group (Exp. Grp) was treated with ABMSC. The cerebral vascular tissue of the patients was treated with hematoxylin-eosin (HE) staining. Immunohistochemical staining was used to identify the levels of Cx43 protein. The concentrations of vascular endothelial growth factor (VEGF), inflammatory factor interleukin-6 (IL6), interleukin-1β (IL1β), tumor necrosis factor (TNFα), and anti-inflammatory factor interleukin-1β (IL1β) were determined by enzyme-linked immunosorbent assay (ELISA). We have found that after treatment of the expression of Cx43 protein, the proportions of grade IV (7.7%), grade III (311.5%), and grade II (3.8%) patients in the Exp. Grp were lower than those in the CG. The proportion of grade I patients in the Exp. Grp (77%) was higher than that in the CG (38.5%). After treatment, the inflammatory factors IL6 (0.97 ± 0.82 pg/mL), IL1β (8.33 ± 1.21 pg/mL), and TNFα (1.73 ± 0.71 pg/mL) in the Exp. Grp were lower than those in the CG. The anti-inflammatory factor IL1β (15.09 ± 4.72 pg/mL) increased in the Exp. Grp compared with the CG (11.25 ± 3.48 pg/mL) post treatment. Intracranial infection, hydrocephalus, hemiplegia, and transient neurological dysfunction in the Exp. Grp were lower than those in the CG, with statistical differences (P < 0.05). Our study suggests that the treatment of autologous bone marrow stem cells (ABMSC) was beneficial to balance the inflammatory response of disorders, reduce the damage of vascular tissue in the brain, and regulate tissue repair by co-acting with various inflammatory factors as compared to traditional surgery. We conclude that the involvement of Cx43 in the occurrence and development of moyamoya. We also have found that the risk factors of intracranial infection after ABMSCT were less as compared to those after conventional surgery.

Bone marrow stem cells therapy alleviates vascular injury in a chronic obstructive pulmonary disease‑obstructive sleep apnea overlap syndrome rat model.

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are highly prevalent potential risk factors for systemic disease. Previous studies have reported that COPD and OSA are major independent risk factors for cardio- or cerebrovascular diseases. The present study aimed to investigate the role of bone marrow mesenchymal stem cells (BMSCs) on vascular injury in a COPD-OSA overlap syndrome (OS) rat model. Rats were randomly divided into three groups: Sham, OS model and BMSC. BMSC localization in major organs was detected via confocal laser fluorescence microscopy, and the aortic tissue pathological changes and related genes were measured using hematoxylin & eosin and Masson staining. Genes associated with vascular endothelial cell injury, including endothelin 1, vascular cell adhesion molecule 1 and endothelial nitric oxide synthase, were detected via reverse transcription-quantitative PCR and western blotting. Apoptosis of vascular endothelial cells was detected using TUNEL and immunofluorescence assays. The endothelial cell marker CD31 in injured vessels was analyzed via immunohistochemistry. BMSCs migrated into the heart, liver, spleen, lung, kidney, brain and aorta in the OS model. The green fluorescence expression of BMSCs demonstrated the highest level in the lung, followed by the aorta. Aortic tissue had a more severe vascular injury and increased apoptosis in the model group compared with the BMSC group. Vascular endothelial cell apoptosis was decreased in the BMSC group compared with the model group. The findings suggested that BMSCs could repair vascular injury by inhibiting endothelial cell damage and apoptosis. These data provide a theoretical basis for the treatment of cardiovascular diseases caused by OS with BMSCs.

Intrathecal autologous bone marrow stem cell therapy in children with autism: A randomized controlled trial.

This study aimed to determine the safety and efficacy of treatment with autologous bone marrow mesenchymal stem cell (BMMSCs) compared with the routine treatment in children with autism spectrum disorder (ASD). In this ethically approved randomized controlled trial, 32 ASD children aged 5-15 years were randomly assigned to receive either autologous BMMSC plus rehabilitation therapy and risperidone (intervention group) or rehabilitation therapy and risperidone (control group). Autologous BMMSCs were intrathecally injected in the intervention group twice in 4 weeks. Patients were assessed using childhood autism rating scale (CARS), Gilliam autism rating scale-second edition (GARS-II), and clinical global impression (CGI) at the baseline, as well as 6 and 12 months after intervention. Overall, 32 patients in two groups of intervention (n = 14) and control (n = 18) completed the study, of which 27 (84.4%) were male. Mean age was 9.50 ± 2.14 years. The improvements in CARS total score, GARS-II autism index, and CGI global improvement showed no significant differences between the groups over 12 months. However, the main effect for time*group interaction was significant regarding the CGI-severity of illness, showing a significantly more pronounced improvement in the intervention group (F = 6.719; P = .002). Intrathecal injection of autologous BMMSCs seems to be safe and feasible, but has limited clinical efficacy in treatment of children with ASD.

Phospholipase Cγ Signaling in Bone Marrow Stem Cell and Relevant Natural Compounds Therapy

Excessive bone resorption has been recognized play a major role in the development of bone-related diseases such as osteoporosis, rheumatoid arthritis, Paget's disease of bone, and cancer. Phospholipase Cγ (PLCγ) family members PLCγ1 and PLCγ2 are critical regulators of signaling pathways downstream of growth factor receptors, integrins, and immune complexes and play a crucial role in osteoclast. Ca2+ signaling has been recognized as an essential pathway to the differentiation of osteoclasts. With growing attention and research about natural occurring compounds, the therapeutic use of natural active plant-derived products has been widely recognized in recent years. In this review, we summarized the recent research on PLCγ signaling in bone marrow stem cells and the use of several natural compounds that were proven to inhibit RANKL-mediated osteoclastogenesis via modulating PLCγ signaling pathways.

Addition of Bone Marrow Stem Cells Therapy Achieves Better Clinical Outcomes and Lower Rates of Disease Progression Compared With Core Decompression Alone for Early Stage Osteonecrosis of the Femoral Head: A Systematic Review and Meta-Analysis.

Osteonecrosis of the femoral head (ONFH) is a cause of hip pain and early joint arthrosis in the young patient. Nonarthroplasty interventions aim to decompress vascular congestion in the femoral head and stimulate new bone growth to prevent progression and collapse. Therefore, the purpose of this study is to evaluate the available evidence on the effect of adjuvant bone marrow stem cells (BMSCs) for early stage ONFH. We performed a systematic review of the MEDLINE, PubMed, Embase, and Cochrane databases in search of published reports comparing the core decompression (CD) with/without adjuvant BMSCs for ONFH. The cohort was divided into two groups: (1) CD with BMSCs (intervention) and (2) CD alone (control subject). The various outcome parameters including hip pain and function, progression of ONFH, rate of revision surgeries, and complications were analyzed. Data were extracted and aggregated for meta-analysis. Cases with staging beyond Ficat II, UPENN II, or ARCO II were excluded. Of the published reports, 16 met our inclusion criteria with an aggregated 583 hips in the intervention and 468 hips in the control subject groups, respectively. Addition of bone marrow cells to CD resulted in lower hip pain score (VAS) (MD = -10.88, 95% CI = -16.84 to -4.92, P = 0.003) and higher HHS score (MD = 5.59, 95% CI = 1.13 to 10.04, P = 0.01) compared with CD alone at the 24-month follow-up. For rates of progression to higher stages, 138 progressed in the intervention group compared with 202 in the control subject group (P = 0.0002). Finally, subsequent patients who required total hip arthroplasty surgery were lower in the intervention group (22.5% versus 42.3%, P = 0.001). Despite heterogeneous and poor data, there is evidence that addition of bone marrow cells to CD appears to result in better clinical outcomes and lower rates of disease progression compared with cored decompression alone. Therapeutic Level III.

Effect of Autologous Bone Marrow Stem Cell Therapy in Patients with Liver Cirrhosis: A Meta-analysis.

Background and Aims: Although autologous bone marrow stem cell (BMSC) transplantation is an effective treatment for liver cirrhosis, there are few reports describing the optimal delivery route and number of injected BMSCs.Methods: A literature search was conducted using PubMed, ISI Web of Science, Cochrane Central Register of Controlled Trials, and EBSCO. A meta-analysis was performed to assess the effect of BMSCs on liver and coagulation function indices. Subgroup analysis was performed based on number of injected BMSCs, delivery route, and length of follow-up.Results: A total of 15 studies were selected from among 1903 potential studies for analysis. Autologous BMSC transplantation significantly improved aspartate aminotransferase, total bilirubin, albumin, prothrombin time, prothrombin activity, prothrombin concentration, Child-Pugh score, and model for end-stage liver disease. In the subgroup analysis of cell numbers, all four of the indices were significantly improved when the number of BMSCs was >4 × 108. The subgroup analysis referring to the delivery route showed that arterial infusion increased the therapeutic effect over venous infusion. Finally, in the subgroup analysis of follow-up length, the results showed that BMSC therapy significantly improved liver function at 2 weeks after transplantation. In addition, this therapy improved coagulation 4 weeks after the transplant, with a maintenance of efficacy for up to 24 weeks.Conclusions: Autologous BMSC therapy is beneficial for liver improvement and coagulation in patients with liver cirrhosis. The therapeutic effect was generated at 2–4 weeks after transplantation. The effect lasted for 24 weeks but no more than 48 weeks. The greatest benefit to patients was observed with a 4 × 108 autologous BMSC transplant via the hepatic artery.

Autologous bone marrow stem cell therapy for patients undergoing coronary artery bypass grafting: A meta-analysis of 14 randomized controlled trials.

Autologous bone marrow stem cell (BMSC) therapy is a novel option for regenerative therapy in patients with ischemic heart disease. The aim of the present meta-analysis was to evaluate the effectiveness of BMSCs combined with coronary artery bypass grafting (CABG). The PubMed, Cochrane Library, EMBASE and Web of Science databases were searched from inception to November 22, 2017 for randomized controlled trials on BMSC therapy combined with CABG. Finally, 14 trials with a total of 596 participants were included. Data were analyzed using a random-effects model. Compared with the control group, the BMSC therapy group exhibited an improvement in the left ventricular (LV) ejection fraction from baseline to follow-up [mean difference (MD)=4.36%; 95% confidence interval (CI): 1.90–6.81%; P<0.01]. Analysis of the pooled results revealed non-significant differences in the LV end-diastolic volume (MD=−6.27 ml; 95% CI: −22.34 to 9.80 ml; P=0.44), LV end-diastolic volume index (MD=−15.11 ml/m2; 95% CI: −31.53 to 1.30 ml/m2; P=0.07), LV end-systolic volume (MD=−11.52 ml; 95% CI: −26.97 to 3.93 ml; P=0.14) and LV end-systolic volume index (MD=−16.56 ml/m2; 95% CI: −37.75 to 4.63 ml/m2; P=0.13) between the BMSC and CABG alone groups. Therefore, autologous BMSC therapy for patients undergoing CABG appears to be associated with an improvement in LV function compared with CABG alone.

Efficacy of Autologous Bone Marrow Mononuclear Cell Transplantation Therapy for Type 2 Diabetes Mellitus: An Updated Meta-Analysis

IntroductionStudies of the effects of stem cell therapy on type 2 diabetes mellitus (T2DM) have not reached consistent results. Our meta-analysis aimed to systematically evaluate the efficacy of autologous bone marrow-derived stem cells (ABM-MNCs) on T2DM.MethodsWe systematically searched PubMed, EMBASE, Web of Science, and the Cochrane Library for studies published between 1980 and May 2018. Two researchers screened the literature independently following the inclusion and exclusion criteria. Meta-analysis of the pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated based on either a fixed- or random-effects model.ResultsWe identified six studies with 206 participants investigating the effects of autologous bone marrow stem cell therapy on T2DM after screening 102 studies found after the initial search. According to the pooled estimates, compared with the control group, after 12-month follow-up the ABM-MNC therapy group had a lower level of HbA1c (MD, − 1.18; 95% CI, − 1.40 to 0.95) and lower required insulin dose (MD, − 2.05; 95% CI, − 3.55 to − 0.55). HbA1c decreased after ABM-MNC therapy compared with before (12 months: MD, − 1.22; 95% CI, − 1.43 to − 1.0). We also observed a significant decrease in insulin requirement after 3-, 6-, 9-, and 12-month follow-up in the ABM-MNC group, respectively.ConclusionAutologous stem cell therapy showed a beneficial effect on T2DM.

HUMAN CD34+ STEM CELL CHIMERISM IN THE HEART PRE-CONDITIONS THE MYOCARDIUM TO PREVENT HEART FAILURE FOLLOWING MYOCARDIAL INFARCTION

Bone marrow stem cell (BMSC) therapy has received great attention for its ability to improve cardiac function post myocardial infarction (MI). Our research has shown that BMSCs from young mice reconstituted and pre-conditioned the myocardium against extensive remodeling post-MI. However, the human homologue demonstrating functional decline with aging is unknown. Human CD34+ BMSCs are hematopoietic and endothelial progenitor cells with potential role in cardiac infarct healing. In current studies, we have evaluated the ability of CD34+ cells, to rejuvenate the bone marrow and repopulate the heart to protect against extensive remodeling post-MI. We have also evaluated the effect of aging on the stem cells’ chimerism. Bone marrow aspirates from 37 patients undergoing open heart surgery (age range 30-82) were collected at the Toronto General Hospital. Mononuclear cells were isolated using Ficoll gradient and BMSC subpopulations were quantified using flow cytometry. Older patients (>60 years old, n=16) had a lower frequency of CD34+ BMSCs (p=0.0008) and CFU colony forming assays showed functional decline in their differentiation potential (p<0.0001). To study the function of CD34+ cells in-vivo, CD34+/- cells were isolated using magnetic cell sorting and were used to reconstitute irradiated immune-deficient 8-12 weeks old NSG mice. Twelve weeks post-reconstitution there was a significant difference in the homing ability of CD34+ (n=7) vs. CD34-(n=6) cells into bone marrow, blood, spleen and heart (p<0.05 for all groups). CD34+ mice reconstituted with cells from younger patients had significantly higher engraftment in blood, spleen and heart (p<0.01 for all groups) as measured by human CD45 chimerism via flow cytometry. Lastly, to study the role of human CD34+ BMSCs in cardiac repair in our humanized mouse model, the mice were subjected to coronary artery ligation at 12 weeks post-reconstitution. At four weeks post-ligation, CD34+ reconstituted mice (n=8) had improved cardiac function, indicated by greater fractional shortening (p=0.003), reduced left ventricle dilation (p=0.02), and reduced infarct expansion (p=0.0002) compared to CD34- reconstituted mice as measured by echocardiography. Furthermore, immunohistochemistry analysis of the cardiac peri-infarct region showed increased number of human CD34-derived CD45+ vessels, indicating their functional role in infarct healing. CD34+ cells are the subpopulation of human BMSCs with reduced frequency and function in older patients. These cells have the ability to repopulate and protect the myocardium from functional decline post-MI in the humanized mouse model. Restoration of aged CD34+ cells prior to cell therapy is a promising avenue for preventing cardiac dysfunction post-MI.

Understanding the Therapeutic Potential of Bone Marrow Stem Cell Therapy in Ischemic Stroke

Despite advances in clinical management, ischemic stroke remains one of the most significant causes of morbidity and mortality in the United States. Stem cell transplantation therapy is emerging as a promising solution to this problem. Ischemic stroke leads to the death of neurons and the surrounding glial cells, leaving patients with significant disabilities. Stem cell therapy has been proven effective in several preclinical studies of induced ischemic stroke, demonstrating neurogenesis, angiogenesis, and improved neural plasticity in animal models. Bone marrow–derived stem cells have shown particular promise in this regard, leading to their application in clinical trials that demonstrated safety and feasibility with limited efficacy. Here, we highlight the potential benefits of cell transplantation therapy for ischemic stroke and review potential mechanisms of action and delivery. We also examine the results of completed clinical trials and the scientific roadblocks that have prevented them from demonstrating greater efficacy. While progress in the clinic has been limited, the future of stem cell therapy is promising. There is still debate as to the methods and applications that would most improve the efficacy of stem cell therapy for ischemic stroke and we review proposed solutions that would address these issues and improve therapeutic designs for future studies.

Pharmacological Mobilization of Endogenous Bone Marrow Stem Cells Promotes Liver Regeneration after Extensive Liver Resection in Rats

Rapid regeneration of the remnant liver is critical for preventing liver failure and promoting recovery after extensive liver resection. Numerous studies have demonstrated the involvement of bone marrow-derived stem cells in liver regeneration and the potential benefits of bone marrow stem cell therapy. To avoid the preparation of stem cells, we proposed in this study to mobilize endogenous bone marrow stem cells pharmacologically with a combination of AMD3100 (A), an antagonist of CXCR4 and low-dose FK506 (F). Here we show that AF combination therapy significantly increased lineage negative (Lin-) CD34+ and Lin-CD133+ stem cells in peripheral blood and enhanced recruitment of CD133+ cells into the remnant liver in a rat model of 85% partial hepatectomy. Recruiting CD133+ stem cells in the remnant liver was associated with increased proliferation of hepatic oval cells and paralleled the increased SDF-1, CXCR4 and HGF expression. Importantly, AF combination therapy increased the number of Ki67 positive hepatocytes and BrdU incorporation in the remnant liver and improved serum levels of albumin. Our results demonstrate that pharmacological mobilization of endogenous bone marrow stem cells with AF combination therapy can enhance endogenous stem cell mobilization to promote liver regeneration and improve liver function after extensive hepatectomy.

Methodological exploration of bone marrow stem cell therapy in acute myocardial infarction - how to achieve greater benefit on cardiac outcomes: A systematic review and meta-analysis.

Clinical trials of intracoronary injection of bone marrow-derived stem cells (BMCs) in patients with acute myocardial infarction (AMI) have revealed promising but variable and modest results. One of the reasons underlying this situation may be the unstandardized preparation of BMCs. The aim of this study was to explore whether methodological differences affect the prognosis of acute myocardial infarction patients who received BMCs transplantation. MEDLINE was searched for randomized controlled trials providing AMI patients with intracoronary BMCs injection or a standard therapy. Changes in cardiac parameters and clinical outcomes were analyzed. Subgroup analyses were conducted according to different methodologies for cell preparation, including supplement for serum or plasma, use of heparin and cell washout. Non-use of serum or plasma in the cell suspension is associated with more reduction in infarct size (IS) and a lower risk of all-cause mortality. Heparin usage could diminish the benefit in reducing IS. All-cause mortality rose significantly without the cell washout procedure when heparin was used. Methodological differences in BMCs preparation as well as the use of heparin and serum/ plasma impact on the prognosis of AMI patients.

Bone marrow transplantation improves motor activity in a mouse model of ataxia.

Ataxias are locomotor disorders that can have an origin both neural and muscular, although both impairments are related. Unfortunately, ataxia has no cure, and the current therapies are aimed at motor re-education or muscular reinforcement. Nevertheless, cell therapy is becoming a promising approach to deal with incurable neural diseases, including neuromuscular ataxias. Here, we have used a model of ataxia, the Purkinje Cell Degeneration (PCD) mutant mouse, to study the effect of healthy (wild-type) bone marrow transplantation on the restoration of defective mobility. Bone marrow transplants (from both mutant and healthy donors) were performed in wild-type and PCD mice. Then, a wide battery of behavioural tests was employed to determine possible motor amelioration in mutants. Finally, cerebellum, spinal cord, and muscle were analysed to study the integration of the transplant-derived cells and the origin of the behavioural changes. Our results demonstrated that the transplant of wild-type bone marrow restores the mobility of PCD mice, increasing their capabilities of movement (52-100% of recovery), exploration (20-71% of recovery), speed (35% of recovery), and motor coordination (25% of recovery). Surprisingly, our results showed that bone marrow transplant notably improves the skeletal muscle structure, which is severely damaged in the mutants, rather than ameliorating the central nervous system. Although a multimodal effect of the transplant is not discarded, muscular improvements appear to be the basis of this motor recovery. Furthermore, the results from our study indicate that bone marrow stem cell therapy can be a safe and effective alternative for dealing with movement disorders such as ataxias.

Autologous bone marrow stem cell therapy in patients with ST-elevation myocardial infarction: a systematic review and meta-analysis

Abstract Background Randomized controlled trials (RCTs) on bone marrow stem cell (BMSC) therapy in ST-elevation myocardial infarction (STEMI) patients have reported conflicting results. Our main objective was to critically appraise and meta-analyze best-available evidence on efficacy and safety of intracoronary administration of autologous BMSC therapy in STEMI patients after primary percutaneous coronary intervention. Methods We conducted a search of MEDLINE, PubMed, EMBASE, CENTRAL, Global Health, CINAHL, and conference proceedings in February 2017. Our primary outcome was all-cause mortality. Secondary and safety outcomes included cardiac death, heart failure, arrhythmias, repeat myocardial infarction, or target vessel revascularizations; or improved health-related quality of life, left ventricular ejection fraction, or infarct size. Summary relative and absolute risks were obtained using random effects models. We also evaluated the strength of evidence. Results A comprehensive database search identified 42 RCTs (3365 STEMI patients). BMSC therapy did not significantly decrease mortality (risk ratio, 0.71; 95% confidence interval, 0.45-1.11; I 2 , 0%; absolute risk reduction, 0.1%; 95% confidence interval, −0.71 to 0.91; 40 trials; 3289 participants; I 2 , 0%; low strength of evidence). BMSC therapy had no effect on secondary or adverse outcomes. Trial sequential analysis for all-cause mortality showed no evidence of a clinically important difference, with a very low probability that future studies can change the current conclusion. Conclusions On the basis of evidence from 42 RCTs published in the past 15 years, we provide conclusive evidence for a lack of beneficial effect for autologous BMSC therapy in patients with STEMI.

GW28-e0652 Meta-analysis of Bone Marrow Stem Cell Therapy on Patients with Chronic Ischemic Heart Disease and Congestive Heart Failure

Bone marrow stem cell therapy as an option for regenerative therapy in chronic ischemic heart disease (IHD) and congestive heart failure was tested in a few randomized controlled trials (RCTs) but with no consistent conclusions regarding salubrious effects in enhancing heart function, remodeling and