Endogenous Neural Stem Cell-induced Neurogenesis after Ischemic Stroke: Processes for Brain Repair and Perspectives.

Ischemic stroke is a very common cerebrovascular accident that occurred in adults and causes higher risk of neural deficits. After ischemic stroke, patients are often left with severe neurological deficits. Therapeutic strategies for ischemic stroke might mitigate neuronal loss due to delayed neural cell death in the penumbra or seek to replace dead neural cells in the ischemic core. Currently, stem cell therapy is the most promising approach for inducing neurogenesis for neural repair after ischemic stroke. Stem cell treatments include transplantation of exogenous stem cells but also stimulating endogenous neural stem cells (NSCs) proliferation and differentiation into neural cells. In this review, we will discuss endogenous NSCs-induced neurogenesis after ischemic stroke and provide perspectives for the therapeutic effects of endogenous NSCs in ischemic stroke. Our review would inform future therapeutic development not only for patients with ischemic stroke but also with other neurological deficits.

Effects of environmental stressors on stem cells.

Environmental toxicants are ubiquitous, and many are known to cause harmful health effects. However, much of what we know or think we know concerning the targets and long-term effects of exposure to environmental stressors is sadly lacking. Toxicant exposure may have health effects that are currently mischaracterized or at least mechanistically incompletely understood. While much of the recent excitement about stem cells (SCs) focuses on their potential as therapeutic agents, they also offer a valuable resource to give us insight into the mechanisms and risks of toxicant effects. Not only as a response to the increasing ethical pressure to reduce animal testing, SC studies allow us valuable insight into the true effects of human exposure to environmental stressors under controlled conditions. We present a review of the history of publications on the effects of environmental stressors on SCs, followed by a consolidation of the literature over the past five years on a subset of key environmental stressors of importance to human health and their effects on both embryonic and tissue SCs. The review will make constructive suggestions as to areas of toxicant research where further studies are needed, as well as making indications of the potential utility for advancing knowledge and directing research on environmental toxicology.

Genomics detects population structure within and between ocean basins in a circumpolar seabird: The white-chinned petrel.

The Southern Ocean represents a continuous stretch of circumpolar marine habitat, but the potential physical and ecological drivers of evolutionary genetic differentiation across this vast ecosystem remain unclear. We tested for genetic structure across the full circumpolar range of the white-chinned petrel (Procellaria aequinoctialis) to unravel the potential drivers of population differentiation and test alternative population differentiation hypotheses. Following range-wide comprehensive sampling, we applied genomic (genotyping-by-sequencing or GBS; 60,709 loci) and standard mitochondrial-marker approaches (cytochrome b and first domain of control region) to quantify genetic diversity within and among island populations, test for isolation by distance, and quantify the number of genetic clusters using neutral and outlier (non-neutral) loci. Our results supported the multi-region hypothesis, with a range of analyses showing clear three-region genetic population structure, split by ocean basin, within two evolutionary units. The most significant differentiation between these regions confirmed previous work distinguishing New Zealand and nominate subspecies. Although there was little evidence of structure within the island groups of the Indian or Atlantic oceans, a small set of highly-discriminatory outlier loci could assign petrels to ocean basin and potentially to island group, though the latter needs further verification. Genomic data hold the key to revealing substantial regional genetic structure within wide-ranging circumpolar species previously assumed to be panmictic.

Proteomic profile of embryonic stem cells with low survival motor neuron protein is consistent with developmental dysfunction.

Spinal muscular atrophy is an autosomal recessive motor neuron disease caused by a genetic defect carried by as many as one in 75 people. Unlike most neurological disorders, we know exactly what the genetic basis is of the disorder, but in spite of this, have little understanding of why the low levels of one protein, survival motor neuron protein, results in the specific progressive die back of only one cell type in the body, the motor neuron. Given the fact that all cells in the body of a patient with spinal muscular atrophy share the same low abundance of the protein throughout development, an appropriate approach is to ask how lower levels of survival motor neuron protein affects the proteome of embryonic stem cells prior to development. Convergent biostatistical analyses of a discovery proteomic analysis of these cells provide results that are consistent with the pathomechanistic fate of the developed motor neuron.

Hypoxic Stress Forces Irreversible Differentiation of a Majority of Mouse Trophoblast Stem Cells Despite FGF4.

Hypoxic, hyperosmotic, and genotoxic stress slow mouse trophoblast stem cell (mTSC) proliferation, decrease potency/stemness, and increase differentiation. Previous reports suggest a period of reversibility in stress-induced mTSC differentiation. Here we show that hypoxic stress at 0.5% O2 decreased potency factor protein by ∼60%-90% and reduced growth to nil. Hypoxia caused a 35-fold increase in apoptosis at Day 3 and a 2-fold increase at Day 6 above baseline. The baseline apoptosis rate was only 0.3%. Total protein was never less than baseline during hypoxic treatment, suggesting 0.5% O2 is a robust, nonmorbid stressor. Hypoxic stress induced ∼50% of trophoblast giant cell (TGC) differentiation with a simultaneous 5- to 6-fold increase in the TGC product antiluteolytic prolactin family 3, subfamily d, member 1 (PRL3D1), despite the presence of fibroblast growth factor 4 (FGF4). Hypoxia-induced TGC differentiation was also supported by potency and differentiation mRNA marker analysis. FGF4 removal at 20% O2 committed cell fate towards irreversible differentiation at 2 days, with similar TGC percentages after an additional 3 days of culture under potency conditions when FGF4 was readded or under differentiation conditions without FGF4. However, hypoxic stress required 4 days to irreversibly differentiate cells. Runted stem cell growth, forced differentiation of fewer cells, and irreversible differentiation limit total available stem cell population. Were mTSCs to respond to stress in a similar mode in vivo, miscarriage might occur as a result, which should be tested in the future.

Comments on Meta-Analyses in General and in Stem Cell Research: An Overview and Cautionary Advice.

Meta-analysis, a tool for contrasting and combining results from different research studies, has been around now for over 40 years. Journal editors are eager to publish the results from meta-analyses, as they propose to represent the integration of best research evidence with clinical expertise and patient values. There are guidelines available, most notably through the Cochrane Collaborative, for investigators to follow in conducting a responsible and, therefore publishable, meta-analysis. Despite the burgeoning popularity of this powerful analytical tool, the procedure is not without its pitfalls. In this study, we advise the readership to familiarize themselves with the most common shortcomings in an effort to help elevate our ability to critically appraise the results of these analyses.

Protein Mobility Shifts Contribute to Gel Electrophoresis Liquid Chromatography Analysis.

Profiling of cellular and subcellular proteomes by liquid chromatography with tandem mass spectrometry (MS) after fractionation by SDS-PAGE is referred to as GeLC (gel electrophoresis liquid chromatography)-MS. The GeLC approach decreases complexity within individual MS analyses by size fractionation with SDS-PAGE. SDS-PAGE is considered an excellent fractionation technique for intact proteins because of good resolution for proteins of all sizes, isoelectric points, and hydrophobicities. Additional information derived from the mobility of the intact proteins is available after an SDS-PAGE fractionation, but that information is usually not incorporated into the proteomic analysis. Any chemical or proteolytic modification of a protein that changes the mobility of that protein in the gel can be detected. The ability of SDS-PAGE to resolve proteins with chemical modifications has not been widely utilized within profiling experiments. In this work, we examined the ability of the GeLC-MS approach to help identify proteins that were modified after a small hairpin RNA-dependent knockdown in an experiment using stable isotope labeling by amino acids in cell culture-based quantitation.

Translating stem cell research from the bench to the clinic: a need for better quality data.

Stem cell therapies show great medical promise, but few new products have made it into the marketplace. The translation of stem and other cell therapies faces not only challenges associated with research and development, but also the challenges of investment funding and regulatory approval. Regulators and investors alike appear to be voicing the same concerns: they see (1) insufficient high-quality data to provide confidence regarding the claims of medical benefit, (2) an insufficient understanding of the mechanism of action, and (3) a lack of identification of essential characteristics for product release criteria and for assuring reproducibility in manufacturing. The ensuing frustration on the part of researchers and developers may be the result of failure to fully comprehend what is required to assure that confidence.