Effect Of Bone Marrow-derived Cells Research Articles

Cell Therapies under Clinical Trials and Polarized Cell Therapies in Pre-Clinical Studies to Treat Ischemic Stroke and Neurological Diseases: A Literature Review.

Stroke remains a major cause of serious disability because the brain has a limited capacity to regenerate. In the last two decades, therapies for stroke have dramatically changed. However, half of the patients cannot achieve functional independence after treatment. Presently, cell-based therapies are being investigated to improve functional outcomes. This review aims to describe conventional cell therapies under clinical trial and outline the novel concept of polarized cell therapies based on protective cell phenotypes, which are currently in pre-clinical studies, to facilitate functional recovery after post-reperfusion treatment in patients with ischemic stroke. In particular, non-neuronal stem cells, such as bone marrow-derived mesenchymal stem/stromal cells and mononuclear cells, confer no risk of tumorigenesis and are safe because they do not induce rejection and allergy; they also pose no ethical issues. Therefore, recent studies have focused on them as a cell source for cell therapies. Some clinical trials have shown beneficial therapeutic effects of bone marrow-derived cells in this regard, whereas others have shown no such effects. Therefore, more clinical trials must be performed to reach a conclusion. Polarized microglia or peripheral blood mononuclear cells might provide promising therapeutic strategies after stroke because they have pleiotropic effects. In traumatic injuries and neurodegenerative diseases, astrocytes, neutrophils, and T cells were polarized to the protective phenotype in pre-clinical studies. As such, they might be useful therapeutic targets. Polarized cell therapies are gaining attention in the treatment of stroke and neurological diseases.

Bone marrow cell migration to the heart in a chimeric mouse model of acute chagasic disease.

BACKGROUND Chagas disease is a public health problem caused by infection with the protozoan Trypanosoma cruzi. There is currently no effective therapy for Chagas disease. Although there is some evidence for the beneficial effect of bone marrow-derived cells in chagasic disease, the mechanisms underlying their effects in the heart are unknown. Reports have suggested that bone marrow cells are recruited to the chagasic heart; however, studies using chimeric mouse models of chagasic cardiomyopathy are rare.OBJECTIVES The aim of this study was to investigate the migration of bone marrow cells to the heart after T. cruzi infection in a model of chagasic disease in chimeric mice.METHODS To obtain chimerical mice, wild-type (WT) C57BL6 mice were exposed to full body irradiation (7 Gy), causing bone marrow ablation. Then, bone marrow cells from green fluorescent protein (GFP)-transgenic mice were infused into the mice. Graft effectiveness was confirmed by flow cytometry. Experimental mice were divided into four groups: (i) infected chimeric (iChim) mice; (ii) infected WT (iWT) mice, both of which received 3 × 104 trypomastigotes of the Brazil strain; (iii) non-infected chimeric (Chim) mice; and (iv) non-infected WT mice.FINDINGS At one-month post-infection, iChim and iWT mice showed first degree atrioventricular block with decreased heart rate and treadmill exercise parameters compared to those in the non-infected groups.MAIN CONCLUSIONS iChim mice showed an increase in parasitaemia, myocarditis, and the presence of amastigote nests in the heart tissue compared to iWT mice. Flow cytometry analysis did not detect haematopoietic progenitor cells in the hearts of infected mice. Furthermore, GFP+ cardiomyocytes were not detected in the tissues of chimeric mice.

Abstract A59: A rodent in situ glioma allograft model to study bone marrow-derived cell migration

Abstract Radiotherapy (RT) induced hypoxia recruits bone marrow-derived cells (BMDCs) to tumors through the upregulation of Stromal Derived Factor-1, a chemokine that binds to receptor CXCR4 present on BMDCs. The infiltration of BMDCs, which includes endothelial progenitors, pericyte progenitors, tumor-associated macrophages, immature monocytes, VEGFR+ hemangiocytes, and CD11b+ myeloid cells has been implicated in supporting tumor establishment by contributing to tumor growth, angiogenesis, vasculogenesis, inflammation, and immune suppression. In this work, we have used a rodent glioma in situ allograft model to study the recruitment/migration of BMDCs post RT. Female albino C57 (8-10 weeks old, Jackson Laboratories) animals underwent +DsRed bone marrow transplant (B6.Cg-Tg(CAG-DsRed*MST)1Nagy/J donor mouse). Following engraftment, glioma cells were cranially implanted with 1x105 glioma cells (GL261-Luc, Perkin Elmer), at an average size of 26.4mm3 indicated by a bioluminescence signal of 5.28x108 photons/sec/cm2/sr, animals underwent 6Gy (RadSource 2000, 250kVp, 25mA) of irradiation limited to a 1cm wide slit centered on the tumor. Bioluminescence (tumor size) and fluorescence imaging (+DsRed BMDCs) was performed prior to and at 1- and 2-weeks post-RT to assess tumor growth and measure the influx of +DsRed BMDCs. In addition, flow cytometry was used to measure the number of +DsRed BMDCs in the tumor and brain. To study the effect of BMDCs in tumor regression, tumors were irradiated at a smaller size (9.3mm3) with 10Gy irradiation. At 1-week post-RT, flow cytometry was used to measure the number of BMDCs (CD45+) in the tumor. In our model 6Gy radiation was able to stall the growth of the tumor. Irradiated tumors did not significantly change in tumor size at either 1- or 2-weeks post irradiation compared to pre-RT size. In addition, irradiated tumors were significantly smaller than untreated tumors (p=0.0008) 1-week post-RT. Using flow cytometry 1-week post irradiation, we observed a significant increase in the number of +DsRed BMDCs in the irradiated tumor (23.5% of cells +DsRed BMDCs) compared to the irradiated brain (6.17% cells +DsRed BMDCs, p=0.03) as well as a significant increase in the tumors (16.6% cells +DsRed BMDCs) compared to the brain (11.1% cells +DsRed BMDCs p=0.02). There was no difference in the number of +DsRed BMDCS in tumors ± irradiation or brains ± irradiation. We found similar results in our tumor regression model using flow cytometry 1-week post-RT; we observed an increase in the number of BMDCs CD45+ in the tumor (~20% of cells CD45+) compared to control tumors (~6% of cells CD45+). Indicating that tumor size at the onset of RT did not effect the migration of BMDCs. Fluorescence imaging did not measure any significant change in the DsRed signal at 1- or 2-weeks post-irradiation. We have successfully shown that post-RT there is an increase in BMDCs migration at 1-week post RT regardless of tumor size at RT. Further experimentation is needed to better elucidate the role of BMDCs in tumor inflammation and immune suppression as well as angiogenesis and vasculogenesis. Our next step is to perform immunohistochemistry on our collected tumor tissue to map out the spatial location of migrated BMDCs within the tumor. Citation Format: Janice A. Zawaski, Tien T. Tang, M Waleed Gaber. A rodent in situ glioma allograft model to study bone marrow-derived cell migration. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A59.

Effects of bone marrow-derived cells and the manipulation of the SDF-1/CXCR4 axis in CKD-associated heart remodeling

Effects of bone marrow-derived cells and the manipulation of the SDF-1/CXCR4 axis in CKD-associated heart remodeling

Long-term effects of bone marrow-derived cells transplantation in patients with acute myocardial infarction: a meta-analysis

Background The long-term effects of bone marrow-derived cells (BMC) transplantation in patients with acute myocardial infarction (AMI) have not been established. The present meta-analysis of randomized controlled trials with follow-up ≥2 years was performed to investigate the long-term effects of BMC therapy in patients after AMI. Methods Specific terms were used to conduct a systematic literature search of MEDLINE, EMBASE, the Cochrane Library and the Cochrane Central Register of Controlled Trials, and the China Biological Medicine Disk database from their inception to March 2012. A standardized protocol was used to extract information, and random effect model was used to analyze all data except major adverse events. Results Five trials comprising 510 patients were included. Compared with controls, BMC therapy significantly improved left ventricular ejection fraction (LVEF) (4.18%, 95% CI: 2.02% to 6.35%, P=0.0002), while mildly but not significantly reduced left ventricular end-systolic volume (-4.47 ml, 95% CI: -10.92 to 1.99, P=0.17) and left ventricular end-diastolic volume (-2.29 ml, 95% CI: -9.96 to 5.39, P =0.56). Subgroup analysis revealed that significant improvement of LVEF induced by BMC therapy could be observed in patients with baseline LVEF ≤42%, but disappeared in those with baseline LVEF >42%. There were trends in favor of BMC therapy for most major clinical adverse events, though most differences were not significant. Conclusions Intracoronary BMC infusion in patients with AMI seems to be safe and may further improve LVEF on top of standard therapy; especially the beneficial effects could last for long term. The findings need to be validated in the future. Chin Med J 2013;126 (2): 353-360

The effect of bone marrow-derived cells on diastolic function and exercise capacity in patients after acute myocardial infarction

BackgroundThe early- to mid-term impact of bone-marrow-derived stem cells (BMC) on diastolic function and exercise capacity after acute myocardial infarction (AMI) remains controversial. We performed a systematic analysis to assess whether BMC transfer is related to an early improvement in diastolic function and exercise capacity after AMI. MethodsRandomized controlled trials (RCTs) of BMC therapy after AMI were extracted from MEDLINE, EMBASE and CENTRAL and analyzed for a change in tissue Doppler annular early (Ea) and late diastolic (Aa) velocities, mitral inflow E velocity to tissue Doppler Ea (E/Ea) ratio, exercise time and exercise capacity. ResultsA total of 365 patients were included from 6 trials. A greater improvement was observed in the E/Ea ratio after 1year in the BMC group compared to the control group. Additionally, the BMC-treated patients had a larger improvement in exercise time, ventilation/CO2 production (VE/VCO2 slope) and respiratory exchange ratio (RER) after 1year. ConclusionThe results indicate that intracoronary BMC treatment in AMI patients leads to a mid-term improvement in diastolic function and exercise capacity.

Effect of autologous bone marrow-derived cells associated with guided bone regeneration or not in the treatment of peri-implant defects

This study investigated the effect of bone marrow-derived cells associated with guided bone regeneration in the treatment of dehiscence bone defects around dental implants. Iliac-derived bone marrow cells were harvested from dogs and phenotypically characterized with regard to their osteogenic properties. After teeth extraction, three implant sites were drilled, dehiscences created and implants placed. Dehiscences were randomly assigned to: bone marrow-derived cells, bone marrow-derived cells + guided bone regeneration, and control (no treatment). After 3 months, implants with adjacent tissues were processed histologically, bone-to-implant contact, bone fill within the threads, new bone area in a zone lateral to the implant, new bone height, and new bone weight at the bottom of the defect were determined. Phenotypic characterization demonstrated that bone marrow-derived cells presented osteogenic potential. Statistically higher bone fill within the threads was observed in both bone marrow-derived cells + guided bone regeneration bone marrow-derived cell groups compared with the control group ( P < 0.05), with no difference between the groups treated with cells ( P > 0.05). For the other parameters (new bone area, bone-to-implant contact, new bone height and new bone weight), only the bone marrow-derived cells + guided bone regeneration group presented higher values compared with the non-treated control ( P < 0.05). Bone marrow-derived cells provided promising results for peri-implantar bone regeneration, although the combined approach seems to be relevant, especially to bone formation out of the implant threads.

Bone marrow transplantation improves hepatic fibrosis in Abcb4−/− mice via Th1 response and matrix metalloproteinase activity

ObjectiveReports on the effects of bone marrow-derived cells on hepatic fibrosis are contradictory. Impaired fibrosis but increased inflammation has recently been demonstrated 10 weeks after bone marrow transplantation (BM-Tx) in...

Cell-based therapies in pulmonary hypertension: who, what, and when?

pulmonary hypertension (PH), diagnosed when mean pulmonary arterial pressure exceeds the upper limits of normal (i.e., >25 mmHg) at rest (2), occurs in a variety of clinical situations and is associated with a broad spectrum of histological patterns and abnormalities. PH is currently classified into five distinct World Health Organization (WHO) groups, based on common clinical parameters, potential etiological mechanisms, and responses to treatment (22). Although any form of PH can contribute to increased patient morbidity and mortality, pulmonary arterial hypertension (PAH) (WHO group 1) is a particularly severe and progressive form associated with right heart failure and premature death (1). At present, therapeutic approaches to stabilize or reverse this debilitating condition involve treatment with one or a combination of up to three specific classes of agents, including prostacyclin analogs, endothelin-1 receptor antagonists, and/or phosphodiesterase-5 inhibitors. Retrospective (meta)analyses of these therapeutic strategies have demonstrated a reduction in mortality with their use (7, 12); however, many experts believe that current PAH treatment is inadequate given the persistently high mortality rate and functional hemodynamic impairment in many patients. These observations have led to continued intensive investigation into pathogenetic mechanisms and many proposals for additional alternative new therapies (20, 24). Among the potential new therapies, increasing interest in the role of endothelial progenitor cells (EPCs) as a cell-based therapy has emerged. However, issues remain regarding what group of PH patients are most likely to benefit from treatment, at what point in the disease is treatment most likely to be successful, and what types of cells should be utilized for therapy.

Bone Marrow–Derived Aldehyde Dehydrogenase–Bright Stem and Progenitor Cells for Ischemic Repair

Adult stem cell populations selected for use in cardiovascular clinical trials typically are mononuclear cell fractions of bone marrow and peripheral blood or cells of specific cell lineages selected by surface markers such as CD34 or CD133. This article describes a potent stem and progenitor cell population identified by an intracellular marker of "stemness" that crosses multiple lineages. Aldehyde dehydrogenase (ALDH)-bright (ALDH(br)) populations isolated from bone marrow contain potent stem and progenitor cells representing all cell types thought to be needed for ischemic repair and include hematopoietic, endothelial, mesenchymal, and neural progenitor cells. An animal model of hindlimb ischemia demonstrated that the ALDH(br) population was highly effective in restoring blood flow to ischemic limbs. Based upon the accumulating evidence for a potential therapeutic effect of bone marrow-derived cells in ischemic disease in humans and the vascular regenerative potential of ALDH(br) cells in the hindlimb model, clinical trials to investigate the use of autologous bone marrow-derived ALDH(br) cells in patients with ischemic heart failure and critical limb ischemia were initiated. Study designs are described. Results of the completed study in patients with critical limb ischemia (CLI) are encouraging and are summarized. Results of 6-month follow-up for the study in ischemic heart failure are pending.

Effects of bone marrow-derived cells on monocrotaline- and hypoxia-induced pulmonary hypertension in mice

BackgroundBone marrow -derived cells (BMDCs) can either limit or contribute to the process of pulmonary vascular remodeling. Whether the difference in their effects depends on the mechanism of pulmonary hypertension (PH) remains unknown.ObjectivesWe investigated the effect of BMDCs on PH induced in mice by either monocrotaline or exposure to chronic hypoxia.MethodsIntravenous administration of the active monocrotaline metabolite (monocrotaline pyrrole, MCTp) to C57BL/6 mice induced PH within 15 days, due to remodeling of small distal vessels. Three days after the MCTp injection, the mice were injected with BMDCs harvested from femurs and tibias of donor mice treated with 5-fluorouracil (3.5 mg IP/animal) to deplete mature cells and to allow proliferation of progenitor cells.ResultsBMDCs significantly attenuated PH as assessed by reductions in right ventricular systolic pressure (20 ± 1 mmHg vs. 27 ± 1 mmHg, P ≤ 0.01), right ventricle weight/left ventricle+septum weight ratio (0.29 ± 0.02 vs. 0.36 ± 0.01, P ≤ 0.03), and percentage of muscularized vessels (26.4% vs. 33.5%, P ≤ 0.05), compared to control animals treated with irradiated BMDCs. Tracking cells from constitutive GFP-expressing male donor mice with anti-GFP antibodies or chromosome Y level measurement by quantitative real-time PCR showed BMDCs in the lung. In contrast, chronically hypoxic mice subjected to the same procedure failed to show improvement in PH.ConclusionThese results show that BMDCs limit pulmonary vascular remodeling induced by vascular injury but not by hypoxia.