Sex of muscle stem cells does not influence potency for cardiac cell therapy

We have previously shown that populations of skeletal muscle-derived stem cells (MDSCs) exhibit sexbased differences for skeletal muscle and bone repair, with female cells demonstrating superior engrafting abilities to males in skeletal muscle while male cells differentiating more robustly toward the osteogenic and chondrogenic lineages. In this study, we tested the hypothesis that the therapeutic capacity of MDSCs transplanted into myocardium is influenced by sex of donor MDSCs or recipient. Male and female MDSCs isolated from the skeletal muscle of 3-week-old mice were transplanted into recipient male or female dystrophin-deficient (mdx) hearts or into the hearts of male SCID mice following acute myocardial infarction. In the mdx model, no difference was seen in engraftment or blood vessel formation based on donor cell or recipient sex. In the infarction model, MDSC-transplanted hearts showed higher postinfarction angiogenesis, less myocardial scar formation, and improved cardiac function compared to vehicle controls. However, sex of donor MDSCs had no significant effects on engraftment, angiogenesis, and cardiac function. VEGF expression, a potent angiogenic factor, was similar between male and female MDSCs. Our results suggest that donor MDSC or recipient sex has no significant effect on the efficiency of MDSC-triggered myocardial engraftment or regeneration following cardiac injury. The ability of the MDSCs to improve cardiac regeneration and repair through promotion of angiogenesis without differentiation into the cardiac lineage may have contributed to the lack of sex difference observed in these models. Copyright © 2009 Cognizant Comm. Corp

Epigenome editing of the CFTR-locus for treatment of cystic fibrosis

Background: Mechanisms governing the diversity of CFTR gene expression throughout the body are complex. Multiple intronic and distal regulatory elements are responsible for regulating differential CFTR expression across tissues. Methods: Drawing on published data, 18 high-priority genomic regions were identified and interrogated for CFTR-enhancer function using CRISPR/dCas9-based epigenome editing tools. Each region was evaluated by dCas9p300 and dCas9KRAB for its ability to enhance or repress CFTR expression, respectively. Results: Multiple genomic regions were tested for enhancer activity using CRISPR/dCas9 epigenome editing. dCas9p300 mediates a significant increase in CFTR mRNA levels when targeted to the promoter and a region 44 kb upstream of the transcriptional start site in a CFTR-low expressing cell line. Multiple gRNAs targeting the promoter induced a robust increase in CFTR protein levels. In contrast, dCas9KRAB-mediated repression is much more robust with 10 of the 18 evaluated genomic regions inducing CFTR protein knockdown. To evaluate the therapeutic efficacy of modulating CFTR gene regulation, dCas9p300 was used to induce elevated levels of CFTR from the endogenous locus in ΔF508/ΔF508 human bronchial epithelial cells. Ussing chamber studies demonstrated a synergistic increase in ion transport in response to CRISPR-induced expression of ΔF508 CFTR mRNA along with VX809 treatment. Conclusions: CRISPR/dCas9-based epigenome-editing provides a previously unexplored tool for interrogating CFTR enhancer function. Here, we demonstrate that therapeutic interventions that increase the expression of CFTR may improve the efficacy of CFTR modulators. A better understanding CFTR regulatory mechanisms could uncover novel therapeutic interventions for the development of cystic fibrosis therapies

Dementia in England: Quantifying and analysing modifiable risk

The prevalence of dementia is set to explode throughout the 21st century. This trend has already started in developed countries and will continue to place heavy pressures on both public health and social care services across the world. No cure for dementia is likely within the foreseeable future, however, medical research highlights the potential to diminish the risk of dementia onset. Over one-third of dementia cases may be preventable if certain risk factors are addressed at the individual, clinical, and population level. This research further explores these modifiable risk factors and quantifies areal risk through the use of a composite index. The index operates at National Health Service Clinical Commission Group level to assess spatial differences across England. Clear spatial patterns are observed between the north and south of the country, and between London and the remainder of the country. The framework adopted in this research provides a firm foundation upon which similar indices could be produced, potentially at finer spatial resolutions, incorporating more informed local knowledge and data on relevant dementia risk factors

Long-term self-renewing human epicardial cells generated from pluripotent stem cells under defined xeno-free conditions

Therapeutic cell differentiatio