ARP2/3 complex is required for directional migration of neural stem cell-derived oligodendrocyte precursors in electric fields

Click on the DOI link to access the article (may not be free).Introduction: The loss of oligodendrocytes in a lesion of the central nervous system causes demyelination and therefore impairs axon function and survival. Transplantation of neural stem cell-derived oligodendrocyte precursor cells (NSC-OPCs) results in increased oligodendrocyte formation and enhanced remyelination. The directional migration of grafted cells to the target can promote the establishment of functional reconnection and myelination in the process of neural regeneration. Endogenous electric fields (EFs) that were detected in the development of the central nervous system can regulate cell migration. Methods: NSCs were isolated from the brains of ARPC2(+/+) and ARPC2(-/-) mouse embryo and differentiated into OPCs. After differentiation, the cultured oligospheres were stimulated with EFs (50, 100, or 200 mV/mm). The migration of OPCs from oligospheres was recorded using time-lapse microscopy. The cell migration directedness and speed were analyzed and quantified. Results: In this study, we found that NSC-OPCs migrated toward the cathode pole in EFs. The directedness and displacement of cathodal migration increased significantly when the EF strength increased from 50 to 200 mV/mm. However, the EF did not significantly change the cell migration speed. We also showed that the migration speed of ARPC2(-/-) OPCs, deficient in the actin-related proteins 2 and 3 (ARP2/3) complex, was significantly lower than that of wild type of OPCs. ARPC2(-/-) OPCs migrated randomly in EFs. Conclusions: The migration direction of NSC-OPCs can be controlled by EFs. The function of the ARP complex is required for the cathodal migration of NSC-OPCs in EFs. EF-guided cell migration is an effective model to understanding the intracellular signaling pathway in the regulation of cell migration directness and motility.This work was supported by LY's start-up funding, Wichita State University, and an Institutional Development Award from the National Institute of General Medical Sciences of the National Institutes of Health under grants P20 GM103418 (to LY) and NIH PO1 GM066311 (to RL)

Chemokine-chemokine receptor pathway as a tumor therapeutic target: the significance of SDF-1CXCR4 pair

Chemokines, a large family of chemotactic cytokines, are the major regulators of immune cell trafficking. The chemokine stromal cell-derived factor-1 (SDF-1, or CXCL12) and its cognate receptor, CXCR4 (CD184), are an important ligand-receptor pair, which play a crucial role in numerous biological processes including hematopoiesis, inflammation, angiogenesis, and cell proliferation. Moreover, accumulating evidence indicates that SDF-1-CXCR4 pair plays important roles in regulating processes essential for tumor biology. Molecular strategies aimed at inhibiting the SDF-1-CXCR4 pathway, such as small peptide CXCR4-specific antagonists, anti-CXCR4 antibodies, and small interfering RNA might therefore prevent tumor progression and metastasis. In the present Dance Round, we focus on (i) the role of the SDF-1-CXCR4 signaling in the regulation of tumor spread, growth, and vascularization, and (ii) the significance of this ligand-receptor pair as a novel therapeutic target for neoplastic disease.Biomedical Reviews 2005; 16: 77-81

Trisomy Correction in Down Syndrome Induced Pluripotent Stem Cells

SummaryHuman trisomies can alter cellular phenotypes and produce congenital abnormalities such as Down syndrome (DS). Here we have generated induced pluripotent stem cells (iPSCs) from DS fibroblasts and introduced a TKNEO transgene into one copy of chromosome 21 by gene targeting. When selecting against TKNEO, spontaneous chromosome loss was the most common cause for survival, with a frequency of ∼10−4, while point mutations, epigenetic silencing, and TKNEO deletions occurred at lower frequencies in this unbiased comparison of inactivating mutations. Mitotic recombination events resulting in extended loss of heterozygosity were not observed in DS iPSCs. The derived, disomic cells proliferated faster and produced more endothelia in vivo than their otherwise isogenic trisomic counterparts, but in vitro hematopoietic differentiation was not consistently altered. Our study describes a targeted removal of a human trisomy, which could prove useful in both clinical and research applications

Accelerating polygon beam with peculiar features

We report on a novel kind of accelerating beams that follow parabolic paths in free space. In fact, this accelerating peculiar polygon beam (APPB) is induced by the spectral phase symmetrization of the regular polygon beam (RPB) with five intensity beam (RPB) with five intensity peaks, and it preserves a peculiar symmetric structure during propagation. Specially, such beam not only exhibits autofocusing property, but also possesses two types of accelerating intensity maxima, i.e., the cusp and spot-point structure, which does not exist in the previously reported accelerating beams. We also provide a detailed insight into the theoretical origin and characteristics of this spatially accelerating beam through catastrophe theory. Moreover, an experimental scheme based on a digital micromirror device (DMD) with the binary spectral hologram is proposed to generate the target beam by precise modulation, and a longitudinal needle-like focus is observed around the focal region. The experimental results confirm the peculiar features presented in the theoretical findings. Further, the APPB is verified to exhibit self-healing property during propagation with either obstructed cusp or spot intensity maxima point reconstructing after a certain distance. Hence, we believe that the APPB will facilitate the applications in the areas of particle manipulation, material processing and optofludics

Endoplasmic Reticulum Stress-Related Factors Protect against Diabetic Retinopathy

The endoplasmic reticulum (ER) is a principal mediator of signal transduction in the cell, and disruption of its normal function (a mechanism known as ER stress) has been associated with the pathogenesis of several diseases. ER stress has been demonstrated to contribute to onset and progression of diabetic retinopathy (DR) by induction of multiple inflammatory signaling pathways. Recent studies have begun to describe the gene expression profile of ER stress-related genes in DR; moreover, genes that play a protective role against DR have been identified. P58IPK was determined to be able to reduce retinal vascular leakage under high glucose conditions, thus protecting retinal cells. It has also been found by our lab that ER-associated protein degradation factors exhibit significantly different expression patterns in rat retinas under sustained high glucose conditions. Future research based upon these collective genomic findings will contribute to our overall understanding of DR pathogenesis as well as identify potential therapeutic targets

Cellular Origins of Regenerating Nodules and Malignancy in the FAH Model of Liver Injury after Bone Marrow Cell Transplantation

In previous reports, we and other groups have shown that proliferating hepatocytes are formed by the fusion of donor hematopoietic cells with host hepatocytes in the Fah−/− model. Thus, it would be interesting to determine whether cell fusion occurs during malignancy. However, it is difficult to demonstrate such processes using this model. Therefore, we established a new strain to study the processes of regenerating nodules and malignancy and their origins. The FAH−/− mouse model was crossed with the ROSAnZ strain and their offspring was genotyped for FAH−/− and ROSAnZ mutations to create a new strain (Fah−/−-ROSAnZ). Using this strain as recipients, we performed bone marrow transplantation experiments. As a result, we could not demonstrate the presence of any epithelial cells except hepatocytes that were of donor origin in regenerating tissue, and no evidence of cell fusion was found in tumors. The hepatic malignancy was of host origin in these mice. There was higher expression of extracellular matrix proteins and more inflammatory cells in liver tumor nodules than in regenerating normal liver nodules. Hepatocytes generated by fusion with bone marrow cells did not form malignant tumors. Extracellular matrix and inflammatory cells had significantly accumulated in liver tumors

Immunity duration of a recombinant adenovirus type-5 vector-based Ebola vaccine and a homologous prime-boost immunisation in healthy adults in China: fi nal report of a randomised, double-blind, placebo-controlled, phase 1 trial

Background The 2013–15 Ebola virus disease epidemic in west Africa greatly accelerated the development of Ebola vaccine. We aimed to analyse the immune persistence induced by one shot of an adenovirus type-5 vector-based Ebola virus vaccine up to 6 months and the eff ect of boosting with a homologous vector in healthy adults in China. Methods In a randomised, double-blind, placebo-controlled, phase 1 clinical trial in one site in Jiangsu Province, China, 120 healthy adults aged 18–60 years received an initial dose of intramuscular adenovirus type-5 Ebola virus vaccine of 4·0 × 10¹⁰ viral particles, 1·6 × 10¹¹ viral particles, or placebo, and were followed up to day 168. Participants were subsequently re-recruited to receive a booster dose of the same vaccine or placebo, in the same dose, at month 6. Women who were pregnant, breastfeeding, or planned to become pregnant during the next month were excluded. Randomisation was conducted by computer-generated block randomisation. Randomisation data were unmasked for interim analysis of the data obtained between days 0–28 but not disclosed to participants or site staff . Safety and immunogenicity analysis were done on the intention-to-treat population. We aimed to assess the safety profi le of the experimental vaccine and the immunity responses to a single-dose immunisation or a homologous prime-boost regimen. Primary outcomes were Ebola glycoprotein-specifi c ELISA antibody responses 28 days post-boost and the occurrences of adverse reactions post-boost. The original trial and the extended booster study were registered with ClinicalTrials.gov, numbers NCT02326194 and NCT02533791, respectively. Findings Between Dec 28, 2014, and Jan 9, 2015, we enrolled 210 volunteers. 90 participants were not randomised due to not meeting inclusion criteria (61), meeting exclusion criteria (4), or withdrawal of consent (25). 120 people were randomly assigned to receive intramuscular Ebola vaccine at 4·0 × 10¹⁰ viral particles (low dose, n=40), Ebola vaccine at 1·6 × 10¹¹ viral particles (high dose, n=40), or placebo (n=40, in two groups of 20). After prime vaccination, the geometric mean titer (GMT) of ELISA EC90 peaked at 682·7 (95% CI 424·3–1098·5) in the low-dose vaccine group and 1305·7 (970·1–1757·2) in the high-dose vaccine group at day 28, and then fell gradually through the next a few months to 575·5 (394·8–838·8) in the high-dose vaccine group and 197·9 (107·9–362·7) in the low-dose vaccine group at day 168. No specific response was recorded in the placebo group with a GMT of 5·0. Of the 120 participants involved in the initial trial, ten participants declined to participate, and 110 were included in the boost immunisation: 38 received the low dose, 35 received the high dose, and 37 received the placebo. At day 28 after boost vaccination, the ELISA EC90 titres rapidly rose to 6110 (95% CI 4705–7935) in the low-dose group and to 11825 (8904–15705) in the high dose group. 78 of 110 participants reported at least one solicited adverse reaction within the fi rst 7 days after booster administration. Both of the groups who received vaccine showed signifi cantly higher incidence of mild or moderate solicited adverse reactions than did the placebo group. Interpretation The adenovirus 5-vectored Ebola vaccine of 1·6 × 10¹¹ viral particles was highly immunogenic and safe. The lower dose of 4·0 × 10¹⁰ viral particles was also safe, but immunogenicity seemed to be more vulnerable to the pre-existing immunity of adenovirus 5. A homologous priming-boosting regimen with adenovirus type-5 Ebola vaccine at 6 months interval was able to elicit greater antibody responses with longer duration. These results support an immunisation strategy to implement a booster injection for a more durable protection against Ebola virus disease