Bone Marrow Stem Cell Treatment for Ischemic Heart Disease in Patients with No Option of Revascularization: A Systematic Review and Meta-Analysis

PMCID: PMC3686792This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis.

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease

Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P&lt;5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease

Transcriptional diversity during lineage commitment of human blood progenitors.

Blood cells derive from hematopoietic stem cells through stepwise fating events. To characterize gene expression programs driving lineage choice, we sequenced RNA from eight primary human hematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. We identified extensive cell type-specific expression changes: 6711 genes and 10,724 transcripts, enriched in non-protein-coding elements at early stages of differentiation. In addition, we found 7881 novel splice junctions and 2301 differentially used alternative splicing events, enriched in genes involved in regulatory processes. We demonstrated experimentally cell-specific isoform usage, identifying nuclear factor I/B (NFIB) as a regulator of megakaryocyte maturation-the platelet precursor. Our data highlight the complexity of fating events in closely related progenitor populations, the understanding of which is essential for the advancement of transplantation and regenerative medicine.The work described in this article was primarily supported by the European Commission Seventh Framework Program through the BLUEPRINT grant with code HEALTH-F5-2011-282510 (D.H., F.B., G.C., J.H.A.M., K.D., L.C., M.F., S.C., S.F., and S.P.G.). Research in the Ouwehand laboratory is further supported by program grants from the National Institute for Health Research (NIHR, www.nihr.ac.uk; to A.A., M.K., P.P., S.B.G.J., S.N., and W.H.O.) and the British Heart Foundation under nos. RP-PG-0310-1002 and RG/09/12/28096 (www.bhf.org.uk; to A.R. and W.J.A.). K.F. and M.K. were supported by Marie Curie funding from the NETSIM FP7 program funded by the European Commission. The laboratory receives funding from the NHS Blood and Transplant for facilities. The Cambridge BioResource (www.cambridgebioresource.org.uk), the Cell Phenotyping Hub, and the Cambridge Translational GenOmics laboratory (www.catgo.org.uk) are supported by an NIHR grant to the Cambridge NIHR Biomedical Research Centre (BRC). The BRIDGE-Bleeding and Platelet Disorders Consortium is supported by the NIHR BioResource—Rare Diseases (http://bioresource.nihr.ac.uk/; to E.T., N.F., and Whole Exome Sequencing effort). Research in the Soranzo laboratory (L.V., N.S., and S. Watt) is further supported by the Wellcome Trust (Grant Codes WT098051 and WT091310) and the EU FP7 EPIGENESYS initiative (Grant Code 257082). Research in the Cvejic laboratory (A. Cvejic and C.L.) is funded by the Cancer Research UK under grant no. C45041/A14953. S.J.S. is funded by NIHR. M.E.F. is supported by a British Heart Foundation Clinical Research Training Fellowship, no. FS/12/27/29405. E.B.-M. is supported by a Wellcome Trust grant, no. 084183/Z/07/Z. Research in the Laffan laboratory is supported by Imperial College BRC. F.A.C., C.L., and S. Westbury are supported by Medical Research Council Clinical Training Fellowships, and T.B. by a British Society of Haematology/NHS Blood and Transplant grant. R.J.R. is a Principal Research Fellow of the Wellcome Trust, grant no. 082961/Z/07/Z. Research in the Flicek laboratory is also supported by the Wellcome Trust (grant no. 095908) and EMBL. Research in the Bertone laboratory is supported by EMBL. K.F. and C.v.G. are supported by FWO-Vlaanderen through grant G.0B17.13N. P.F. is a compensated member of the Omicia Inc. Scientific Advisory Board. This study made use of data generated by the UK10K Consortium, derived from samples from the Cohorts arm of the project.This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on 26/9/14 in volume 345, number 6204, DOI: 10.1126/science.1251033. This version will be under embargo until the 26th of March 2015

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

5-Azacytidine Is Insufficient For Cardiogenesis In Human Adipose-Derived Stem Cells

<p>Abstract</p> <p>Background</p> <p>Adipose tissue is a source of multipotent adult stem cells and it has the ability to differentiate into several types of cell lineages such as neuron cells, osteogenic cells and adipogenic cells. Several reports have shown adipose-derived stem cells (ASCs) have the ability to undergo cardiomyogenesis. Studies have shown 5-azacytidine can successfully drive stem cells such as bone marrow derived stem cells to differentiate into cardiomyogenic cells. Therefore, in this study, we investigated the effect 5-azacytidine on the cardiogenic ability of ASCs.</p> <p>Methods</p> <p>The cardiogenic potential of ASCs was analysed by studying the morphological changes after induction, the changes in the cardiogenic genes expression i.e. GATA4, MLC-2v, MLC-2a, NKX2.5, β-MHC, α-MHC, Atrial natriuretic peptide (ANP), Connexin 43, Cardiac Troponin C, Cardiac Troponin I and myocyte enhancer factor (MEF2C) and the changes of embryonic stem cells genes expression at P5 and P10 using quantitative PCR.</p> <p>Results</p> <p>Our results showed that the induced ASCs did not show significant morphological difference compared to the non-induced ASCs. While quantitative PCR data indicated that most cardiogenic genes and stemness genes expression level decreased after induction at P5 and P10.</p> <p>Conclusion</p> <p>5-azacytidine is insufficient for the cardiogenic induction of the ASCs.</p

Meta-Analysis of Percutaneous Endomyocardial Cell Therapy in Patients with Ischemic Heart Failure by Combination of Individual Patient Data (IPD) of ACCRUE and Publication-Based Aggregate Data

Individual patient data (IPD)-based meta-analysis (ACCRUE, meta-analysis of cell-based cardiac studies, NCT01098591) revealed an insufficient effect of intracoronary cell-based therapy in acute myocardial infarction. Patients with ischemic heart failure (iHF) have been treated with reparative cells using percutaneous endocardial, surgical, transvenous or intracoronary cell delivery methods, with variable effects in small randomized or cohort studies. The objective of this meta-analysis was to investigate the safety and efficacy of percutaneous transendocardial cell therapy in patients with iHF. Two investigators extracted the data. Individual patient data (IPD) (n = 8 studies) and publication-based (n = 10 studies) aggregate data were combined for the meta-analysis, including patients (n = 1715) with chronic iHF. The data are reported in accordance with PRISMA guidelines. The primary safety and efficacy endpoints were all-cause mortality and changes in global ejection fraction. The secondary safety and efficacy endpoints were major adverse events, hospitalization and changes in end-diastolic and end-systolic volumes. Post hoc analyses were performed using the IPD of eight studies to find predictive factors for treatment safety and efficacy. Cell therapy was significantly (p < 0.001) in favor of survival, major adverse events and hospitalization during follow-up. A forest plot analysis showed that cell therapy presents a significant benefit of increasing ejection fraction with a mean change of 2.51% (95% CI: 0.48; 4.54) between groups and of significantly decreasing end-systolic volume. The analysis of IPD data showed an improvement in the NYHA and CCS classes. Cell therapy significantly decreased the end-systolic volume in male patients; in patients with diabetes mellitus, hypertension or hyperlipidemia; and in those with previous myocardial infarction and baseline ejection fraction ≤ 45%. The catheter-based transendocardial delivery of regenerative cells proved to be safe and effective for improving mortality and cardiac performance. The greatest benefit was observed in male patients with significant atherosclerotic co-morbidities

Protocol for collection and separation of bone marrow mononuclear cells in Chlorocebus aethiops

Abstract: Chlorocebus aethiops is a species of non-human primate frequently used in biomedical research. Some research involves this species as an experimental model for various diseases and possible treatment with stem cells. The bone marrow is one of the main sources of these cells and provides easy access. The aim of this study was to standardize the protocol of collection and separation of bone marrow in C. aethiops. Ten animals were submitted to puncture of bone marrow with access to the iliac crest and cell separation by density gradient. The bone marrow of C. aethiops had an average of 97% viability. From the results achieved, we can conclude that C. aethiops is an excellent model to obtain and isolate mononuclear cells from bone marrow, fostering several studies in the field of cell therapy

c-kitpos GATA-4 High Rat Cardiac Stem Cells Foster Adult Cardiomyocyte Survival through IGF-1 Paracrine Signalling

Resident c-kit positive (c-kitpos) cardiac stem cells (CSCs) could be considered the most appropriate cell type for myocardial regeneration therapies. However, much is still unknown regarding their biological properties and potential.We produced clones of high and low expressing GATA-4 CSCs from long-term bulk-cultured c-kitpos CSCs isolated from adult rat hearts. When c-kitpos GATA-4 high expressing clonal CSCs (cCSCs) were co-cultured with adult rat ventricular cardiomyocytes, we observed increased survival and contractility of the cardiomyocytes, compared to cardiomyocytes cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low expressing cCSCs. When analysed by ELISA, the concentration of IGF-1 was significantly increased in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-cultures and there was a significant correlation between IGF-1 concentration and cardiomyocyte survival. We showed the activation of the IGF-1 receptor and its downstream molecular targets in cardiomyocytes co-cultured with c-kitpos GATA-4 high cCSCs but not in cardiomyocytes that were cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low cCSCs. Addition of a blocking antibody specific to the IGF-1 receptor inhibited the survival of cardiomyocytes and prevented the activation of its signalling in cardiomyocytes in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-culture system. IGF-1 supplementation or IGF-1 high conditioned medium taken from the co-culture of c-kitpos GATA-4 high cCSCs plus cardiomyocytes did extend the survival and contractility of cardiomyocytes cultured alone and cardiomyocytes co-cultured with c-kitpos GATA-4 low cCSCs.c-kitpos GATA-4 high cCSCs exert a paracrine survival effect on cardiomyocytes through induction of the IGF-1R and signalling pathway