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Memory T (TM) cells play an important role in the long-term defense against pathogen reinvasion. However, it is still unclear how these cells receive the crucial signals necessary for their longevity and homeostatic turnover. To understand how TM cells receive these signals, we infected mice with lymphocytic choriomeningitis virus (LCMV) and examined the expression sites of neural cadherin (N-cadherin) by immunofluorescence microscopy. We found that N-cadherin was expressed in the surroundings of the white pulps of the spleen and medulla of lymph nodes (LNs). Moreover, TM cells expressing high levels of killer cell lectin-like receptor G1 (KLRG1), a ligand of N-cadherin, were co-localized with N-cadherin+ cells in the spleen but not in LNs. We then blocked N-cadherin in vivo to investigate whether it regulates the formation or function of TM cells. The numbers of CD127hiCD62Lhi TM cells in the spleen of memory P14 chimeric mice declined when N-cadherin was blocked during the contraction phase, without functional impairment of these cells. In addition, when CD127loKLRG1hi TM cells were adoptively transferred into anti–N-cadherin–treated mice compared with control mice, the number of these cells was reduced in the bone marrow and LNs, without functional loss. Taken together, our results suggest that N-cadherin participates in the development of CD127hiCD62Lhi TM cells and homing of CD127loKLRG1hi TM cells to lymphoid organs.

Summary Spermatogonial transplantation has been used as a standard assay for spermatogonial stem cells (SSCs). After transplantation into the seminiferous tubules, SSCs transmigrate through the blood-testis barrier (BTB) between Sertoli cells and settle in a niche. Unlike in the repair of other self-renewing systems, SSC transplantation is generally performed after complete destruction of endogenous spermatogenesis. Here, we examined the impacts of recipient conditioning on SSC homing. Germ cell ablation downregulated the expression of glial cell line-derived neurotrophic factor, which has been shown to attract SSCs to niches, implying that nonablated niches would attract SSCs more efficiently. As expected, SSCs colonized nonablated testes when transplanted into recipients with the same genetic background. Moreover, although spermatogenesis was arrested at the spermatocyte stage in Cldn11-deficient mice without a BTB, transplantation not only enhanced donor colonization but also restored normal spermatogenesis. The results show promise for the development of a new transplantation strategy to overcome male infertility., Graphical abstract, Highlights • Spermatogonial stem cells (SSCs) can engraft in nonablated testes • GFRA1+ spermatogonia are relatively resistant to busulfan • GDNF is downregulated after germ cell deficiency • SSC transplantation into Cldn11-deficient testes restores spermatogenesis, In this article, Shinohara and colleagues show that spermatogonial stem cells can colonize and produce offspring in nonablated recipients.

Background Dystrophinopathy, a common neuromuscular disorder caused by the absence of dystrophin, currently lacks effective treatments. Systemic transplantation of adipose-derived stem cells (ADSCs) is a promising treatment approach, but its low efficacy remains a challenge. Chemokine system-mediated stem cell homing plays a critical role in systemic transplantation. Here, we investigated whether overexpression of a specific chemokine receptor could improve muscle homing and therapeutic effects of ADSC systemic transplantation in dystrophic mice. Methods We analysed multiple microarray datasets from the Gene Expression Omnibus to identify a candidate chemokine receptor and then evaluated the protein expression of target ligands in different tissues and organs of dystrophic mice. The candidate chemokine receptor was overexpressed using the lentiviral system in mouse ADSCs, which were used for systemic transplantation into the dystrophic mice, followed by evaluation of motor function, stem cell muscle homing, dystrophin expression, and muscle pathology. Results Chemokine-profile analysis identified C–C chemokine receptor (CCR)2 as the potential target for improving ADSC homing. We found that the levels of its ligands C–C chemokine ligand (CCL)2 and CCL7 were higher in muscles than in other tissues and organs of dystrophic mice. Additionally, CCR2 overexpression improved ADSC migration ability and maintained their multilineage-differentiation potentials. Compared with control ADSCs, transplantation of those overexpressing CCR2 displayed better muscle homing and further improved motor function, dystrophin expression, and muscle pathology in dystrophic mice. Conclusions These results demonstrated that CCR2 improved ADSC muscle homing and therapeutic effects following systemic transplantation in dystrophic mice.

In altricial birds, to address which cues are used by parents to recognize their offspring, and when they switch between cues during reproduction, it has not been well determined. In this study, we address this question in a Tibetan population of the azure-winged magpie Cyanopica cyanus, by examining the dependence of parents on a nest’s spatial position in offspring recognition. During the egg and nestling phases, azure-winged magpie nests were translocated to new positions across various distances from their original site, and parental responses to the translocated nests were investigated. Our findings show that a nest’s spatial position is not connected with the survival of its young, but might be used as a cue in parental offspring recognition. When nests are translocated to a new position within a certain distance, parents could recognize their nests and returned to resume their parenting behaviors. Parental dependence on the nest’s spatial position in offspring recognition is higher during the egg phase than during the nestling phase, and it decreases with the growth of nestlings. After nestlings reach a certain age, the nest’ s spatial position was no longer used by parents as the single cue for offspring recognition. These findings suggest that azure-winged magpies switch their cues in offspring recognition during the different stages of reproduction. After parent–offspring communication has been established, the offspring’s phenotypic traits may become a more reliable cue than the nest’s spatial position in offspring recognition.

Selectins are key to mediating interactions involved in cellular adhesion and migration, underlying processes such as immune responses, metastasis, and transplantation. Selectins are composed of a lectin domain, an epidermal growth factor (EGF)-like domain, multiple short consensus repeats (SCRs), a transmembrane domain, and a cytoplasmic tail. It is well-established that the lectin and EGF domains are required to mediate interactions with ligands; however, the contributions of the other domains in mediating these interactions remain obscure. Using various E-selectin constructs produced in a newly developed silkworm-based expression system and several assays performed under both static and physiological flow conditions, including flow cytometry, glycan array analysis, surface plasmon resonance, and cell-rolling assays, we show here that a reduction in the number of SCR domains is correlated with a decline in functional E-selectin binding to hematopoietic cell E- and/or L-selectin ligand (HCELL) and P-selectin glycoprotein ligand-1 (PSGL-1). Moreover, the binding was significantly improved through E-selectin dimerization and by a substitution (A28H) that mimics an extended conformation of the lectin and EGF domains. Analyses of the association and dissociation rates indicated that the SCR domains, conformational extension, and dimerization collectively contribute to the association rate of E-selectin–ligand binding, whereas just the lectin and EGF domains contribute to the dissociation rate. These findings provide the first evidence of the critical role of the association rate in functional E-selectin–ligand interactions, and they highlight that the SCR domains have an important role that goes beyond the structural extension of the lectin and EGF domains.

Homing based gene drives (HGD) possess the potential to spread linked cargo genes into natural populations and are poised to revolutionize population control of animals. Given that host encoded genes have been identified that are important for pathogen transmission, targeting these genes using guide RNAs as cargo genes linked to drives may provide a robust method to prevent disease transmission. However, effectiveness of the inclusion of additional guide RNAs that target separate genes has not been thoroughly explored. To test this approach, we generated a split-HGD in Drosophila melanogaster that encoded a drive linked effector consisting of a second gRNA engineered to target a separate host-encoded gene, which we term a gRNA-mediated effector (GME). This design enabled us to assess homing and knockout efficiencies of two target genes simultaneously, and also explore the timing and tissue specificity of Cas9 expression on cleavage/homing rates. We demonstrate that inclusion of a GME can result in high efficiency of disruption of both genes during super-Mendelian propagation of split-HGD. Furthermore, both genes were knocked out one generation earlier than expected indicating the robust somatic expression of Cas9 driven by Drosophila germline-limited promoters. We also assess the efficiency of ‘shadow drive’ generated by maternally deposited Cas9 protein and accumulation of drive-induced resistance alleles along multiple generations, and discuss design principles of HGD that could mitigate the accumulation of resistance alleles while incorporating a GME.

The high mortality of COVID-19 is mostly attributed to acute respiratory distress syndrome (ARDS), whose histopathological correlate is diffuse alveolar damage (DAD). Furthermore, severe COVID-19 is often accompanied by a cytokine storm and a disrupted response of the adaptive immune system. Studies aiming to depict this dysregulation have mostly investigated the peripheral cell count as well as the functionality of immune cells. We investigated the impact of SARS-CoV-2 on antigen-presenting cells using multiplexed immunofluorescence. Similar to MERS-CoV and SARS-CoV, SARS-CoV-2 appears to be impairing the maturation of dendritic cells (DCs). DC maturation involves a switch in surface antigen expression, which enables the cells' homing to lymph nodes and the subsequent activation of T-cells. As quantitative descriptions of the local inflammatory infiltrate are still scarce, we compared the cell population of professional antigen-presenting cells (APC) in the lungs of COVID-19 autopsy cases in different stages of DAD. We found an increased count of myeloid dendritic cells (mDCs) in later stages. Interestingly, mDCs also showed no significant upregulation of maturation markers in DAD-specimens with high viral load. Accumulation of immature mDCs, which are unable to home to lymph nodes, ultimately results in an inadequate T-cell response.

C-X-C chemokine receptor type 4 (CXCR4), initially recognized as a co-receptor for HIV, contributes to several disorders, including the WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome. CXCR4 binds to its ligand SDF-1 to make an axis involved in the homing property of stem cells. This study aimed to employ WHIM syndrome pathogenesis as an inspirational approach to reinforce cell therapies. Wild type and WHIM-type variants of the CXCR4 gene were chemically synthesized and cloned in the pCDH-513B-1 lentiviral vector. Molecular cloning of the synthetic genes was confirmed by DNA sequencing, and expression of both types of CXCR4 at the protein level was confirmed by western blotting in HEK293T cells. Human adipose-derived mesenchymal stem cells (Ad-MSCs) were isolated, characterized, and subjected to lentiviral transduction with Wild type and WHIM-type variants of CXCR4. The presence of copGFP-positive MSCs confirmed the high efficiency of transduction. The migration ability of both groups of transduced cells was then assessed by transwell migration assay in the presence or absence of a CXCR4-blocking agent. Our qRT-PCR results showed overexpression of CXCR4 at mRNA level in both groups of transduced MSCs, and expression of WHIM-type CXCR4 was significantly higher than Wild type CXCR4 ( P

BackgroundImmune cells in the tumor microenvironment have prognostic value. In preclinical models, recruitment and infiltration of these cells depends on immune cell homing (ICH) genes such as chemokines, cell adhesion molecules, and integrins. We hypothesized ICH ligands CXCL9-11 and CCL2-5 would be associated with intratumoral T-cells, while CXCL13 would be more associated with B-cell infiltrates.MethodsSamples of human melanoma were submitted for gene expression analysis and immune cells identified by immunohistochemistry. Associations between the two were evaluated with unsupervised hierarchical clustering using correlation matrices from Spearman rank tests. Univariate analysis performed Mann–Whitney tests.ResultsFor 119 melanoma specimens, analysis of 78 ICH genes revealed association among genes with nonspecific increase of multiple immune cell subsets: CD45+, CD8+and CD4+T-cells, CD20+B-cells, CD138+plasma cells, and CD56+NK-cells. ICH genes most associated with these infiltrates included ITGB2, ITGAL, CCL19, CXCL13, plus receptor/ligand pairs CXCL9 and CXCL10 with CXCR3; CCL4 and CCL5 with CCR5. This top ICH gene expression signature was also associated with genes representing immune-activation and effector function. In contrast, CD163+M2-macrophages was weakly associated with a different ICH gene signature.ConclusionThese data do not support our hypothesis that each immune cell subset is uniquely associated with specific ICH genes. Instead, a larger set of ICH genes identifies melanomas with concordant infiltration of B-cell and T-cell lineages, while CD163+M2-macrophage infiltration suggesting alternate mechanisms for their recruitment. Future studies should explore the extent ICH gene signature contributes to tertiary lymphoid structures or cross-talk between homing pathways.

Camels (Camelus dromedarius) are known to have good navigational abilities and can find their home after displacement to far places; however, there are no studies available on the navigational strategies employed by the camels in homing behavior. Thus, the aim of this study was to investigate these strategies by displacing female camels equipped with GPS trackers 6 km away from home to totally unfamiliar locations. The experiments comprised displacing nursing or non-nursing female camels 6 km from their living pens to an unfamiliar release site. Some camels were taken to the release site on foot, others were hauled on a truck, both during daytime and nighttime. Displacements journeys were either in a straight direction to the release points, or they consisted of a convoluted path. As a result, camels that had straight outward journeys were able to return home efficiently and rather directly, but camels that had convoluted trips to the release point failed to do so. Moreover, impairing olfactory, visual, and auditory inputs by using mouth/nose muzzles, eye covers and headphones did not affect homing ability. Based on these experiments the most likely hypothesis is that during their small-scale round trips the camels relied on path integration, and that this strategy is disrupted when the camels were subjected to disorientation procedures before release., Summary: The study reports a series of experiments aimed at understanding the orientation mechanisms of Arabian camels in the Rub' al Khali desert in the UAE. Camels were taken either on foot or inside trucks to unfamiliar release points, some 6 km from their living pens. Camels homed successfully after simple displacements but seemed lost after a looping journey. It is inferred that camels use path integration, dead reckoning, after short simple displacements.

Introns are ubiquitous in eukaryotic genomes and have long been considered as ‘junk RNA’ but the huge energy expenditure in their transcription, removal, and degradation indicate that they may have functional significance and can offer evolutionary advantages. In fungi, plants and algae introns make a significant contribution to the size of the organellar genomes. Organellar introns are classified as catalytic self-splicing introns that can be categorized as either Group I or Group II introns. There are some biases, with Group I introns being more frequently encountered in fungal mitochondrial genomes, whereas among plants Group II introns dominate within the mitochondrial and chloroplast genomes. Organellar introns can encode a variety of proteins, such as maturases, homing endonucleases, reverse transcriptases, and, in some cases, ribosomal proteins, along with other novel open reading frames. Although organellar introns are viewed to be ribozymes, they do interact with various intron- or nuclear genome-encoded protein factors that assist in the intron RNA to fold into competent splicing structures, or facilitate the turn-over of intron RNAs to prevent reverse splicing. Organellar introns are also known to be involved in non-canonical splicing, such as backsplicing and trans-splicing which can result in novel splicing products or, in some instances, compensate for the fragmentation of genes by recombination events. In organellar genomes, Group I and II introns may exist in nested intronic arrangements, such as introns within introns, referred to as twintrons, where splicing of the external intron may be dependent on splicing of the internal intron. These nested or complex introns, with two or three-component intron modules, are being explored as platforms for alternative splicing and their possible function as molecular switches for modulating gene expression which could be potentially applied towards heterologous gene expression. This review explores recent findings on organellar Group I and II introns, focusing on splicing and mobility mechanisms aided by associated intron/nuclear encoded proteins and their potential roles in organellar gene expression and cross talk between nuclear and organellar genomes. Potential application for these types of elements in biotechnology are also discussed.

Intestinal intraepithelial lymphocytes (IELs) are one of the largest populations of lymphocytes and comprised of heterogeneous populations with varying phenotypes and physiological/pathological functions. IELs located between the basolateral surfaces of the epithelial cells and then potentially provide a first line of immune defense against enteric pathogens, although, the precise roles of each IEL populations are not well defined. A variety of molecules are involved in the IEL-homing to the intestinal epithelium. Conventional IELs originate from circulating T cells activated in lymphoid organs and imprinted for gut homing. On the other hand, unconventional IELs derive from thymocytes and migrate to the intestinal epithelium, although, some of them may arise extrathymically. Regarding the interaction between IELs and epithelial cells, IELs are known to be highly motile and actively migrate along the basement membrane, suggesting their roles in immune surveillance. In addition, there has been growing evidence to support that IELs are involved in the pathogenesis of gut disorders such as celiac disease and inflammatory bowel diseases. In this review, we provide a comprehensive overview of IEL dynamics and their clinical significance.

Karaciğer hücresi nakli, karaciğer yetmezliğindeortotopik hücre nakline güçlü bir alternatiftir. Son yıllarda, kök hücrelerindoğalarının, kinetiklerinin ve yenilenen karaciğer bölgesinde etkili birşekilde toplanmalarının sağlanmasının anlaşılması için hatırı sayılır gayretlersarf edilmektedir. Mesenkimal kökhücreler karaciğer yenilenme sürecini modüle eden ümit verici hücrekaynaklarından bir tanesidir. Bu çalışma, mezenkimal kök hücrelerin sıçanlardatoll benzeri reseptör (TLR) ifadesini değiştirmek suretiyle karaciğer immünyanıtını nasıl etkileyebildiklerini ve karaciğer yenilenmesi esnasındayenilenme potansiyelini arttırabildiklerini belirlemek için gerçekleştirilmiştir. Normal vekaraciğerleri kısmen çıkarılmış sıçanlar, sıçan kemik iliğinden elde edilip çoğaltılanmesenkimal kök hücreler ile muamele edilmişlerdir. Mesenkimal kök hücrelerintoplanması Eş Zamanlı Polimeraz Zincir Reaksiyonu (RT-PCR), Floresan AktiviteHücre Ayırma (FACS), ve Immunfloresan Boyama (IFS) ile doğrulanmıştır. Sham vekaraciğeri kısmen alınmış sıçan grupları arasındaki farklılığın istatistikianalizinde Student's t-testi kullanılmıştır. Elde edilensonuçlar mezenkimal kök hücrelerindeçeşitli TLR’lerin ifade edildiklerini ve bu hücrelerin yenilenme esnasındatoplanmalarının meydana gelen hasarın zamanlamasına bağlı olduğunugöstermiştir. Normal sıçanların kemik iliğinden izole edilen mezenkimal kökhücreler hasarlı karaciğerde enjeksiyon sonrası 3. günde görülmüşlerdir.Hasarsız hayvanların karaciğer kesitlerinde işaretli bir mezenkimal kök hücregörülmemiştir. Mezenkimal kök hücre uygulaması TLR2, 3 ve 9'un ifadesininanlamlı bir şekilde değiştirirken yenilenen karaciğere göç etme yeteneklerinidevam ettirmişlerdir. Sonuçlar, karaciğeryenilenmesi esnasında mezenkimal kök hücre uygulamasının, hücrelerinuygulandığı hasarsız karaciğer parçalarında TLR’lerin ifadelerini değiştirmeyoluyla immün yanıtı modüle ettiğini ortaya koymaktadır. TLR ifadesindeki budeğişim kısmı hepatoktemi sonrası yenilenme sürecine katkı sağlayabilirniteliktedir., Liver cell transplantation is a powerful alternative toorthotopic cell transplantation in the treatment of liver failures. Recently,considerable effort is being channeled to understand the nature and kinetics ofdirecting stem cells to effectively accumulate at the regenerating liver site.Mesenchymal stem cells are one of the promising cell sources modulating liverregeneration process. Present wasdesigned to study how mesenchymal stem cells might modulate liver immunebehaviors by changing Toll-like receptor (TLR) expression and increaseregenerative potential during liver regeneration in rats. Normal and partially hepatectomized rats were treated withmesenchymal stem cells isolated and expanded from rat bone marrows.Accumulation of mesenchymal stem cells was confirmed by Real Time-PolymeraseChain Reaction (RT-PCR),Fluorescence-Activated Cell Sorting (FACS), and Immunofluorescence Staining (IFS). Student's t-test analysiswas used to evaluate the significance of differences between sham and partiallyhepatectomized rat groups. Our results showed that mesenchymal stem cells expressedseveral TLRs, and their accumulation during regeneration was depended on thetiming of injury. Mesenchymal stem cells isolated from bone marrow of normalrats were observed at the injured liver 3 days after the injection. There wereno labeled mesenchymal stem cells in the liver sections of the uninjuredanimals. Mesenchymal stem cell administration significantly altered theexpression of TLR2, 3 and 9 while retaining their migration potential toregenerating liver.Our findings implicated thatmesenchymal stem cell administration during liver regeneration modulate theimmune response through changing the expression of the TLRs in the remainingliver parts into which the cells are recruited or infused. This alteration maycontribute to the regeneration process following partial hepatectomy.

Time of day is recognized as an important behaviour modulator of wild animals mainly via physical environmental changes such as temperature and light intensity. These temporal factors can also affect animal movements (i.e., changes of locations) and consequent distribution. However, while it is commonly observed in diverse taxa that an animal’s attendance at a specific site concentrates within a narrow time window, how time influences the route selections of traveling animals in the course of their movements through to the end point is still not well understood. In this study, we quantified temporal and spatial patterns in the homing paths of streaked shearwaters Calonectris leucomelas, which are present at the breeding colony exclusively after sunset, to investigate how time constrains their movement strategy for homing from at-sea foraging areas. We tracked the foraging trips using GPS loggers in chick-rearing seasons for five years. In addition, in one year we conducted displacement experiments, releasing birds at sea at three different times of the day (midday, sunset and night-time) to impose time constraints on homeward movements. The movement paths revealed that the time of sunset was key to their decision of timing and in route selections during homing. Most birds returning from foraging trips reached the coastal area around sunset by adjusting travel timing and directions, despite variation in foraging areas, and flew along the coastline to the breeding island. Meanwhile, most birds released offshore stopped flights around sunset and waited on the water surface for sunrise before restarting their homeward movements. Birds therefore avoid offshore traveling at night, appearing to preferentially use diurnal cues for homing at sea. This study demonstrates the importance of timing as well as geographic features for homing decisions of streaked shearwaters and confirms that both spatial and temporal cognitive abilities are well developed in seabirds.

Chronic low back pain (LBP) remains a challenging condition to treat, and especially to cure. If conservative treatment approaches fail, the current "gold standard" for intervertebral disc degeneration (IDD)-provoked back pain is spinal fusion. However, due to its invasive and destructive nature, the focus of orthopedic research related to the intervertebral disc (IVD) has shifted more towards cell-based therapeutic approaches. They aim to reduce or even reverse the degenerative cascade by mimicking the human body's physiological healing system. The implementation of progenitor and/or stem cells and, in particular, the delivery of mesenchymal stromal cells (MSCs) has revealed significant potential to cure the degenerated/injured IVD. Over the past decade, many research groups have invested efforts to find ways to utilize these cells as efficiently and sustainably as possible. This narrative literature review presents a summary of achievements made with the application of MSCs for the regeneration of the IVD in recent years, including their preclinical and clinical applications. Moreover, this review presents state-of-the-art strategies on how the homing capabilities of MSCs can be utilized to repair damaged or degenerated IVDs, as well as their current limitations and future perspectives.

Homing-based gene drives, engineered using CRISPR/Cas9, have been proposed to spread desirable genes throughout populations. However, invasion of such drives can be hindered by the accumulation of resistant alleles. To limit this obstacle, we engineer a confinable population modification home-and-rescue (HomeR) drive in Drosophila targeting an essential gene. In our experiments, resistant alleles that disrupt the target gene function were recessive lethal and therefore disadvantaged. We demonstrate that HomeR can achieve an increase in frequency in population cage experiments, but that fitness costs due to the Cas9 insertion limit drive efficacy. Finally, we conduct mathematical modeling comparing HomeR to contemporary gene drive architectures for population modification over wide ranges of fitness costs, transmission rates, and release regimens. HomeR could potentially be adapted to other species, as a means for safe, confinable, modification of wild populations.

Significance While inflammatory chemokines, constitutively produced by pathologic regions, are pivotal for attracting reparative stem cells, one would certainly not want to further “inflame” a diseased brain by instilling such molecules. Exploiting the fact that receptors for such cytokines (G protein-coupled receptors [GPCR]) possess two “pockets”—one for binding, the other for signaling—we created a synthetic GPCR-agonist that maximizes interaction with the former and narrows that with the latter. Homing is robust with no inflammation. The peptide successfully directed the integration of human induced pluripotent stem cell derivatives (known to have muted migration) in a model of a prototypical neurodegenerative condition, ameliorating symptomatology., A transplanted stem cell’s engagement with a pathologic niche is the first step in its restoring homeostasis to that site. Inflammatory chemokines are constitutively produced in such a niche; their binding to receptors on the stem cell helps direct that cell’s “pathotropism.” Neural stem cells (NSCs), which express CXCR4, migrate to sites of CNS injury or degeneration in part because astrocytes and vasculature produce the inflammatory chemokine CXCL12. Binding of CXCL12 to CXCR4 (a G protein-coupled receptor, GPCR) triggers repair processes within the NSC. Although a tool directing NSCs to where needed has been long-sought, one would not inject this chemokine in vivo because undesirable inflammation also follows CXCL12–CXCR4 coupling. Alternatively, we chemically “mutated” CXCL12, creating a CXCR4 agonist that contained a strong pure binding motif linked to a signaling motif devoid of sequences responsible for synthetic functions. This synthetic dual-moity CXCR4 agonist not only elicited more extensive and persistent human NSC migration and distribution than did native CXCL 12, but induced no host inflammation (or other adverse effects); rather, there was predominantly reparative gene expression. When co-administered with transplanted human induced pluripotent stem cell-derived hNSCs in a mouse model of a prototypical neurodegenerative disease, the agonist enhanced migration, dissemination, and integration of donor-derived cells into the diseased cerebral cortex (including as electrophysiologically-active cortical neurons) where their secreted cross-corrective enzyme mediated a therapeutic impact unachieved by cells alone. Such a “designer” cytokine receptor-agonist peptide illustrates that treatments can be controlled and optimized by exploiting fundamental stem cell properties (e.g., “inflammo-attraction”).

Background Limited knowledge of stem cell therapies` mechanisms of action hampers their sustainable implementation into the clinic. Specifically, the interactions of transplanted stem cells with the host vasculature and its implications for their therapeutic efficacy are not elucidated. We tested whether adhesion receptors and chemokine receptors on stem cells can be functionally modulated, and consequently if such modulation may substantially affect therapeutically relevant stem cell interactions with the host endothelium. Methods We investigated the effects of cationic molecule polyethylenimine (PEI) treatment with or without nanoparticles on the functions of adhesion receptors and chemokine receptors of human bone marrow-derived Mesenchymal Stem Cells (MSC). Analyses included MSC functions in vitro, as well as homing and therapeutic efficacy in rodent models of central nervous system´s pathologies in vivo. Findings PEI treatment did not affect viability, immunomodulation or differentiation potential of MSC, but increased the CCR4 expression and functionally blocked their adhesion receptors, thus decreasing their adhesion capacity in vitro. Intravenously applied in a rat model of brain injury, the homing rate of PEI-MSC in the brain was highly increased with decreased numbers of adherent PEI-MSC in the lung vasculature. Moreover, in comparison to untreated MSC, PEI-MSC featured increased tumour directed migration in a mouse glioblastoma model, and superior therapeutic efficacy in a murine model of stroke. Interpretation Balanced stem cell adhesion and migration in different parts of the vasculature and tissues together with the local microenvironment impacts their therapeutic efficacy. Funding Robert Bosch Stiftung, IZEPHA grant, EU grant 7 FP Health

Ants can navigate by comparing the currently perceived view with memorised views along a familiar foraging route. Models regarding route-following suggest the views are stored and recalled independently of the sequence in which they occur. Hence, the ant only needs to evaluate the instantaneous familiarity of the current view to obtain a heading direction. This study investigates whether ant homing behaviour is influenced by alterations in the sequence of views experienced along a familiar route, using the frequency of stop-and-scan behaviour as an indicator of the ant's navigational uncertainty. Ants were trained to forage between their nest and a feeder which they exited through a short channel before proceeding along the homeward route. In tests, ants were collected before entering the nest and released again in the channel, which was placed either in its original location or halfway along the route. Ants exiting the familiar channel in the middle of the route would thus experience familiar views in a novel sequence. Results show that ants exiting the channel scan significantly more when they find themselves in the middle of the route, compared to when emerging at the expected location near the feeder. This behaviour suggests that previously encountered views influence the recognition of current views, even when these views are highly familiar, revealing a sequence component to route memory. How information about view sequences could be implemented in the insect brain as well as potential alternative explanations to our results are discussed.

International audience; Pax7 expression marks stem cells in developing skeletal muscles and adult satellite cells during homeostasis and muscle regeneration. The genetic determinants that control the entrance into the myogenic program and the appearance of PAX7+ cells during embryogenesis are poorly understood. SIX homeoproteins are encoded by the Sine oculis homeobox related Six1-Six6 genes in vertebrates. Six1, Six2, Six4 and Six5 are expressed in the muscle lineage. Here we tested the hypothesis that Six1 and Six4 could participate in the genesis of myogenic stem cells. We show that fewer PAX7+ cells occupy a satellite cell position between the myofiber and its associated basal lamina in Six1 and Six4 (s1s4KO) at E18. However, PAX7+ cells are detected in remaining muscle masses present in the epaxial region of the double mutant embryos and are able to divide and contribute to muscle growth. To further characterize the properties of s1s4KO PAX7+ cells, we analyzed their transcriptome and tested their properties after transplantation in adult regenerating tibialis anterior (TA) muscle. Mutant stem cells form hypotrophic myofibers that are not innervated but retain the ability to self-renew.

Unusual amongst dung beetles, Scarabaeus galenus digs a burrow that it provisions by making repeated trips to a nearby dung pile. Even more remarkable is that these beetles return home moving backwards, with a pellet of dung between their hind legs. Here, we explore the strategy that S. galenus uses to find its way home. We find that, like many other insects, they use path integration to calculate the direction and distance to their home. If they fail to locate their burrow, the beetles initiate a distinct looping search behaviour that starts with a characteristic sharp turn, we have called a ‘turning point’. When homing beetles are passively displaced or transferred to an unfamiliar environment, they initiate a search at a point very close to the location of their fictive burrow—that is, a spot at the same relative distance and direction from the pick-up point as the original burrow. Unlike other insects, S. galenus do not appear to supplement estimates of the burrow location with landmark information. Thus, S. galenus represents a rare case of a consistently backward-homing animal that does not use landmarks to augment its path integration strategy.

Bone marrow endothelium plays an important role in the homing of hematopoietic stem and progenitor cells upon transplantation, but surprisingly little is known on how the bone marrow endothelial cells regulate local permeability and hematopoietic stem and progenitor cells transmigration. We show that temporal loss of vascular endothelial-cadherin function promotes vascular permeability in BM, even upon low-dose irradiation. Loss of vascular endothelial-cadherin function also enhances homing of transplanted hematopoietic stem and progenitor cells to the bone marrow of irradiated mice although engraftment is not increased. Intriguingly, stabilizing junctional vascular endothelial-cadherin in vivo reduced bone marrow permeability, but did not prevent hematopoietic stem and progenitor cells migration into the bone marrow, suggesting that hematopoietic stem and progenitor cells use the transcellular migration route to enter the bone marrow. Indeed, using an in vitro migration assay, we show that human hematopoietic stem and progenitor cells predominantly cross bone marrow endothelium in a transcellular manner in homeostasis by inducing podosome-like structures. Taken together, vascular endothelial-cadherin is crucial for BM vascular homeostasis but dispensable for the homing of hematopoietic stem and progenitor cells. These findings are important in the development of potential therapeutic targets to improve hematopoietic stem and progenitor cell homing strategies.

Determining bee flight capacity is crucial for developing management strategies for bee conservation and/or crop pollination and purposes. In this study, we determined the flight distance of the stingless bee Melipona fasciculata using the radiofrequency identification (RFID) technology. For this, we conducted two translocation experiments using workers equipped with RFID microsensors: (1) release of bees at seven distances between 100 and 3000 m from experimental colonies in Belém, Brazil, and (2) at six distances between 1500 and 10,000 m at Carajás National Forest Reserve. Return rates of workers were negatively correlated to release distance, with typical flight distances of 2 km, but a maximum homing distance of 10 km. Use of RFID tags revealed how past experiments may have greatly underestimated homing abilities of stingless bees. Made available in DSpace on 2020-04-18T00:55:01Z (GMT). No. of bitstreams: 1 NunesSilva2020ArticleRadiofrequencyIdentificationRF.pdf: 1323919 bytes, checksum: f4f9452df5cf30549fbdb12260b3821a (MD5) Previous issue date: 2020

International audience; Solitary foraging ants rely on vision when travelling along routes and when pinpointing their nest. We tethered foragers of Myrmecia croslandi on a trackball and recorded their intended movements when the trackball was located on their normal foraging corridor (on-route), above their nest and at a location several metres away where they have never been before (off-route). We found that at on-and off-route locations, most ants walk in the nest or foraging direction and continue to do so for tens of metres in a straight line. In contrast, above the nest, ants walk in random directions and change walking direction frequently. In addition, the walking direction of ants above the nest oscillates on a fine scale, reflecting search movements that are absent from the paths of ants at the other locations. An agent-based simulation shows that the behaviour of ants at all three locations can be explained by the integration of attractive and repellent views directed towards or away from the nest, respectively. Ants are likely to acquire such views via systematic scanning movements during their learning walks. The model predicts that ants placed in a completely unfamiliar environment should behave as if at the nest, which our subsequent experiments confirmed. We conclude first, that the ants' behaviour at release sites is exclusively driven by what they currently see and not by information on expected outcomes of their behaviour; and second, that navigating ants might continuously integrate attractive and repellent visual memories. We discuss the benefits of such a procedure.

Adequate homing is essential for the survival of any animal when it leaves its home to find prey or a mate. There are several strategies by which homing can be carried out: (a) retrace the outbound path; (b) use a 'cognitive map'; or (c) use path integration (PI). Here, I review the state of the art of research on spiders (Araneae) and whip spiders (Amblypygi) homing behaviour. The main strategy described in the literature as being used by these arachnids is PI. Behavioural and neural substrates of PI are described in a small group of spider families (Agelenidae, Lycosidae, Gnaphosidae, Ctenidae and Theraphosidae) and a whip spider family (Phrynidae). In spiders, the cues used to detect the position of the animal relative to its home are the position of the sun, polarized light patterns, web elasticity and landmarks. In whip spiders, the cues used are olfactory, tactile and, with a more minor role, visual. The use of a magnetic field in whip spiders has been rejected both with field and laboratory studies. Concerning the distance walked in PI, the possibility of using optic flow and idiothetic information in spiders is considered. The studies about outbound and inbound paths in whip spiders seem to suggest they do not follow the PI rules. As a conclusion, these arachnids' navigation relies on multimodal cues. We have detailed knowledge about the sensory origin (visual, olfactory, mechanosensory receptors) of neural information, but we are far from knowing the central neural structures where sensory information is integrated.

The spermatogonial transplantation technique was developed by Dr. Ralph Brinster in 1994. Transplanted spermatogonial stem cells (SSCs) produce germ cell colonies after microinjection into the seminiferous tubules of infertile mice. This technique provided the first functional assay for SSCs. Although it became possible to produce transgenic animals using this transplantation technique in 2001, the lack of SSC culture systems prevented efficient genetic manipulation. To overcome this problem, a long-term SSC culture technique was developed in 2003. Cultured SSCs, designated as germline stem cells, allow drug selection of transfected SSCs, and knockout mice were produced in 2006. Using these techniques, it is now possible to address basic biological questions of SSC biology. They also open up new possibilities for male germline manipulation. In this review, we will briefly summarize our findings on SSCs and discuss unresolved issues that remain to be addressed. Keywords: Germline stem cell, Spermatogonial stem cell, Self-renewal, Fertility, Pluripotency, Homing

There are currently limitations in stem cell therapy due to the low rate of homing and proliferation of cells following transplantation. The present study was designed to investigate the effects of Tenascin‑C (TN‑C) on bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanisms. BMSCs were obtained from C57BL/6 mice. The survival and proliferation of BMSCs was analyzed by Cell Counting Kit‑8 assay, migration was evaluated using the Transwell method, and differentiation was assessed by immunocytochemistry and immunofluorescence. In addition, the levels of proteins were detected by western blotting. High concentrations of TN‑C promoted the migration of BMSCs. H2O2 at concentrations of 60‑90 µmol/ml induced cell death in BMSCs, and thus, it was used to simulate oxidative stress in the microenvironment of acute myocardial infarction (AMI). High concentrations of TN‑C were able to protect BMSCs from cell death, and promoted the migration of BMSCs (P

// Dan Qin 1, * , Yi Yan 1, * , Bian Hu 2, * , Wanpo Zhang 1 , Hanmin Li 3 , Xiaodong Li 3 , Shenghui Liu 1 , Depeng Dai 1 , Xiongji Hu 1 , Xingxu Huang 2 and Lisheng Zhang 1 1 College of Veterinary Medicine, University of Huazhong Agricultural, Wuhan 430070, People’s Republic of China 2 School of Life Science and Technology, Shanghai Tech University, Pudong New Area, Shanghai 201210, People’s Republic of China 3 Hepatic Disease Institute, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430061, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Lisheng Zhang, email: lishengzhang@mail.hzau.edu.cn Keywords: rat; Wisp2; Cxcr4; BMSCs; homing Received: June 10, 2017 Accepted: October 02, 2017 Published: October 24, 2017 ABSTRACT Liver regeneration/repair is a compensatory regrowth following acute liver failure, and bone marrow-derived mesenchyme stem cell (BMSC) transplantation is an effective therapy that promotes liver regeneration/repair. Wnt1 inducible signaling pathway protein 2 (Wisp2) is highly expressed in BMSCs, however, its function remains unclear. In this work, we used clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein -9 nuclease (CRISPR/Cas9) genome editing technology to knockdown Wisp2 in BMSCs, and these modified cells were then transplanted into rats which were induced by the 2-AAF/PH. By linking the expression of Cas9 to green fluorescent protein (GFP), we tracked BMSCs in the rats. Disruption of Wisp2 inhibited the homing of BMSCs to injured liver and aggravated liver damage as indicated by remarkably high levels of ALT and AST. Moreover, the key factor in BMSC transplantation, C-X-C chemokine receptor type 4 (Cxcr4), was down-regulated in the Wisp2 depleted BMSCs and had a lower expression in the livers of the corresponding rats. By tracing the GFP marker, more BMSCs were observed to differentiate into CD31 positive endothelial cells in the functional Wisp2 cells but less in the Wisp2 gene disrupted cells. In summary, Wisp2 promotes the homing of BMSCs through Cxcr4 related signaling during liver repair in rats.

Recently, certain studies have demonstrated in vitro that prostaglandin E2 (PGE2) promotes human cluster of differentiation (CD)34+ cell homing. However, the sub‑type receptors activated by PGE2 are unknown, as the PGE2 receptor EP1-4 subtypes (EP1-4) are expressed on the membrane of human CD34+ cells. Based on the above, the present study aimed to screen the receptor subtype activity by PGE2 to promote human CD34+ cell homing. It was observed that human CD34+ cells expressed the four PGE2 sub‑receptors, particularly EP2 and 4. PGE2 increased EP2 and 4 mRNA expression significantly, while EP1 and 3 mRNA exhibited no significant alteration. PGE2, EP2 agonist (EP2A), and EP4A upregulated C‑X‑C chemokine receptor 4 mRNA and protein expression in human CD34+ cells, and promoted stromal cell‑derived factor 1α (SDF‑1α) expression in bone marrow mesenchymal stem cells (BMMSCs). These phenomena were inhibited by the associated receptor antagonists. PGE2, EP2A, and EP4A facilitated human CD34+ cell migration towards SDF‑1α and BMMSCs. The results of the present study suggested that PGE2 promoted human CD34+ cell homing through EP2 and 4 receptors in vitro.

Summary Cell therapy continues to attract growing interest as a promising approach to treat a variety of diseases. Mesenchymal stem cells (MSCs) have been one of the most intensely studied candidates for cell therapy. Since the homing capacity of MSCs is an important determinant of effective MSC-based therapy, the enhancement of homing efficiency is essential for optimizing the therapeutic outcome. Furthermore, trafficking of endogenous MSCs to damaged tissues, also referred to as endogenic stem cell homing, and the subsequent participation of MSCs in tissue regeneration are considered to be a natural self-healing response. Therefore, strategies to stimulate and reinforce the mobilisation and homing of MSCs have become a key point in regenerative medicine. The current review focuses on advances in the mechanisms and factors governing trafficking of MSCs, and the relationship between MSC mobilisation and skeletal diseases, providing insights into strategies for their potential translational implications.

There is a need for new interventions against the ongoing burden of vector-borne diseases such as malaria and dengue. One suggestion has been to develop genes encoding effector molecules that block parasite development within the vector, and then use the nuclease-based homing reaction as a form of gene drive to spread those genes through target populations. If the effector gene reduces the fitness of the mosquito and does not contribute to the drive, then loss-of-function mutations in the effector will eventually replace functional copies, but protection may nonetheless persist sufficiently long to provide a public health benefit. Here, we present a quantitative model allowing one to predict the duration of protection as a function of the probabilities of different molecular processes during the homing reaction, various fitness effects, and the efficacy of the effector in blocking transmission. Factors that increase the duration of protection include reducing the frequency of pre-existing resistant alleles, the probability of nonrecombinational DNA repair, the probability of homing-associated loss of the effector, the fitness costs of the nuclease and effector, and the completeness of parasite blocking. For target species that extend over an area much larger than the typical dispersal distance, the duration of protection is expected to be highest at the release site, and decrease away from there, eventually falling to zero, as effector-less drive constructs replace effector-containing ones. We also model an alternative strategy of using the nuclease to target an essential gene, and then linking the effector to a sequence that restores the essential function and is resistant to the nuclease. Depending upon parameter values, this approach can prolong the duration of protection. Our models highlight the key design criteria needed to achieve a desired level of public health benefit.

International audience; Gathering information on both individual movement and gene flow is rarely possible when studying dispersal among populations in fish species. It is, however, possible to assess both at a reasonable cost in Salmo trutta L. on the Atlantic coast of Europe where the facultative anadromous species is composed of discrete populations of brown trout residents occupying distinct river systems, but exchanging phenotypically distinguishable sea trout migrants. We performed two kinds of genetic analyses using individual microsatellite genotypes: the stock identification of sea trout entering each corridor and the estimates of effective dispersal through each corridor. We observed that individual movement (nonlocal individuals of each source population ranging from 4% to 35% of the sea trout run) never translates into effective dispersal except in one of four migratory corridors examined. The likely origin of this uniquely detected gene flow event is discussed in the light of well-documented migratory fish management actions undertaken in the past in the studied area.

Summary To discover small molecules that modulate hematopoietic cell homing after adoptive transfer, we created a transgenic zebrafish expressing firefly luciferase downstream of the ubiquitin promoter (ubi:luc) to serve as a hematopoietic donor. Bioluminescence imaging (BLI) was used to detect and follow ubi:luc hematopoietic cells that homed to the marrow as early as 1 day post-transplant. BLI was able to detect the biological effect of prostaglandin E2 on early homing/engraftment of donor hematopoietic cells. This system was utilized in a functional screen of small molecules to enhance homing/engraftment. We discovered a phytosterol, ergosterol, that could increase hematopoietic cell homing in zebrafish and mice. In addition, ergosterol increased CXCR4 expression and promoted expansion of Lin−SCA-1+KIT+ cells in vitro. We have demonstrated the utility of in vivo BLI to non-invasively monitor donor hematopoietic cell activity in adult zebrafish as a functional screen for mediators of cellular homing., Highlights • Bioluminescent imaging (BLI) can track engrafting hematopoietic cells • BLI can be used for screening of enhancers of hematopoietic cell homing • Using BLI, ergosterol was found to increase hematopoietic cell homing • Ergosterol affects hematopoietic progenitor migration, growth, and viability in vitro, Accelerating cell homing after adoptive transfer may expediate recovery after hematopoietic transplant. Lund and colleagues developed a novel zebrafish model utilizing bioluminescent imaging to track hematopoietic cell homing, thus allowing for a functional screening approach of small molecule libraries.

Cancer is the second leading cause of death worldwide and patients are in urgent need of therapies that can effectively target cancer with minimal off-target side effects. Exosomes are extracellular nano-shuttles that facilitate intercellular communication between cells and organs. It has been established that tumor-derived exosomes contain a similar protein and lipid composition to that of the cells that secrete them, indicating that exosomes might be uniquely employed as carriers for anti-cancer therapeutics. Methods: We isolated exosomes from two cancer cell lines, then co-cultured each type of cancer cells with these two kinds of exosomes and quantified exosome. HT1080 or Hela exosomes were systemically injected to Nude mice bearing a subcutaneous HT1080 tumor to investigate their cancer-homing behavior. Moreover, cancer cell-derived exosomes were engineered to carry Doxil (a common chemotherapy drug), known as D-exo, were used to detect their target and therapeutic efficacy as anti-cancer drugs. Exosome proteome array analysis were used to reveal the mechanism underly this phenomenon. Results: Exosomes derived from cancer cells fuse preferentially with their parent cancer cells, in vitro. Systemically injected tumor-derived exosomes home to their original tumor tissues. Moreover, compared to Doxil alone, the drug-loaded exosomes showed enhanced therapeutic retention in tumor tissues and eradicated them more effectively in nude mice. Exosome proteome array analysis revealed distinct integrin expression patterns, which might shed light on the underlying mechanisms that explain the exosomal cancer-homing behavior. Conclusion: Here we demonstrate that the exosomes' ability to target the parent cancer is a phenomenon that opens up new ways to devise targeted therapies to deliver anti-tumor drugs.

Adoptive transfer of natural killer (NK) cells can induce remission in patients with relapsed/refractory leukemia and myeloma. However, to date, clinical efficacy of NK cell immunotherapy has been limited to a sub-fraction of patients. Here we show that steps incorporated in the ex vivo manipulation/production of NK cell products used for adoptive infusion, such as over-night IL-2 activation or cryopreservation followed by ex vivo expansion, drastically decreases NK cell surface expression of the bone marrow (BM) homing chemokine receptor CXCR4. Reduced CXCR4 expression was associated with dampened in vitro NK cell migration toward its cognate ligand stromal-derived factor-1α (SDF-1α). NK cells isolated from patients with WHIM syndrome carry gain-of-function (GOF) mutations in CXCR4 (CXCR4R334X). Compared to healthy donors, we observed that NK cells expanded from WHIM patients have similar surface levels of CXCR4 but have a much stronger propensity to home to BM compartments when adoptively infused into NOD-scid IL2Rgammanull (NSG) mice. Therefore, in order to augment the capacity of adoptively infused NK cells to home to the BM, we genetically engineered ex vivo expanded NK cells to express the naturally occurring GOF CXCR4R334X receptor variant. Transfection of CXCR4R334X-coding mRNA into ex vivo expanded NK cells using a clinically applicable method consistently led to an increase in cell surface CXCR4 without altering NK cell phenotype, cytotoxic function, or compromising NK cell viability. Compared to non-transfected and wild type CXCR4-coding mRNA transfected counterparts, CXCR4R334X-engineered NK cells had significantly greater chemotaxis toward SDF-1α in vitro. Importantly, expression of CXCR4R334X on expanded NK cells resulted in significantly greater BM homing following adoptive transfer into NSG mice compared to non-transfected NK cell controls. Collectively, these data suggest up-regulation of cell surface CXCR4R334X on ex vivo expanded NK cells via mRNA transfection represents a novel approach to improve homing and target NK cell-based immunotherapies to BM where hematological malignancies reside.

Human mesenchymal/stromal stem cells (hMSC) are the most promising cell source for adult cell therapies in regenerative medicine. Many clinical trials have reported the use of autologous transplantation of hMSCs in several disorders, but with limited results. To exert their potential, hMSCs could exhibit efficient homing and migration toward lesion sites among other effects, but the underlying process is not clear enough. To further increase the knowledge, we studied the co-regulation between hypoxia-regulated genes and miRNAs. To this end, we investigated the miRNA expression profile of healthy hMSCs in low oxygen/nutrient conditions to mimic ischemia and compared with cells of patients suffering from critical limb ischemia (CLI). miRNAs are small, highly conserved, non-coding RNAs, skilled in the control of the target&rsquo, s expression level in a fine-tuned way. After analyzing the miRNOme in CLI-derived hMSC cells and healthy controls, and intersecting the results with the mRNA expression dataset under hypoxic conditions, we identified two miRNAs potentially relevant to the disease: miR-29b as a pathological marker of the disease and miR-638 as a therapeutic target. This study yielded a deeper understanding of stem cell biology and ischemic disorders, opening new potential treatments in the future.

Mesenchymal stem cells (MSCs) are promising candidates for bone regeneration therapies due to their plasticity and easiness of sourcing. MSC-based treatments are generally considered a safe procedure, however, the long-term results obtained up to now are far from satisfactory. The main causes of these therapeutic limitations are inefficient homing, engraftment, and osteogenic differentiation. Many studies have proposed modifications to improve MSC engraftment and osteogenic differentiation of the transplanted cells. Several strategies are aimed to improve cell resistance to the hostile microenvironment found in the recipient tissue and increase cell survival after transplantation. These strategies could range from a simple modification of the culture conditions, known as cell-preconditioning, to the genetic modification of the cells to avoid cellular senescence. Many efforts have also been done in order to enhance the osteogenic potential of the transplanted cells and induce bone formation, mainly by the use of bioactive or biomimetic scaffolds, although alternative approaches will also be discussed. This review aims to summarize several of the most recent approaches, providing an up-to-date view of the main developments in MSC-based regenerative techniques.

Endothelial progenitor cells (EPCs) are a subtype of bone marrow–derived progenitor cells. Stromal cell-derived factor 1 (SDF-1)-mediated EPC mobilization from bone marrow to areas of ischemia plays an important role in angiogenesis. Previous studies have reported that advanced glycation endproducts (AGEs), which are important mediators of diabetes-related vascular pathology, may impair EPC migration and homing, but the mechanism is unclear. Syndecan-4 (synd4) is a ubiquitous heparan sulfate proteoglycan receptor on the cell surface, involved in SDF-1-dependent cell migration. The extracellular domain of synd4 (ext-synd4) is shed in the context of acute inflammation, but the shedding of ext-synd4 in response to AGEs is undefined. Here we investigated changes in ext-synd4 on EPCs in response to AGEs, focusing on the influence of impaired synd4 signaling on EPC migration and homing. We found decreased full length and increased residue of synd4 in cells incubated with AGEs, with concomitant increase in the soluble fragment of ext-synd4 in the cell medium. EPCs from patients with type 2 diabetes expressed less ext-synd4 as assessed by Western blotting. Flow cytometry analysis showed less ext-synd4 on circulating CD34+ peripheral blood mononuclear cells, of which EPCs form a subgroup. We then explored the role of synd4 in EPC migration and homing. Impaired migration of synd4-deficient EPCs was observed by a 2D-chemotaxis slide. Furthermore, poor homing of synd4−/− EPCs was observed in a mouse model of lower limb ischemia. This study demonstrates that the shedding of synd4 from EPCs plays a key role in AGE-mediated dysfunction of EPC migration and homing.

The process by which prostate cancer cells non-randomly disseminate to the bone to form lethal metastases remains unknown. Metastasis is the ultimate consequence of the long-range dispersal of a cancer cell from the primary tumor to a distant secondary site. In order to metastasize, the actively emigrating cell must move. Movement ecology describes an individual's migration between habitats without the requirement of conscious decision-making. Specifically, this paradigm describes four interacting components that influence the dynamic process of metastasis: (1) the microenvironmental pressures exerted on the cancer cell, (2) how the individual cell reacts to these external pressures, (3) the phenotypic switch of a cell to gain the physical traits required for movement, and (4) the ability of the cancer cell to navigate to a specific site. A deeper understanding of each of these components will lead to the development of novel therapeutics targeted to interrupt previously unidentified steps of metastasis.

Over the past 2 decades, therapies based on mesenchymal stem cells (MSC) have been tested to treat several types of diseases in clinical studies, due to their potential for tissue repair and regeneration. Currently, MSC-based therapy is considered a biologically safe procedure, with the therapeutic results being very promising. However, the benefits of these therapies are not stable in the long term, and the final outcomes manifest with high inter-patient variability. The major cause of these therapeutic limitations results from the poor engraftment of the transplanted cells. Researchers have developed separate strategies to improve MSC engraftment. One strategy aims at increasing the survival of the transplanted MSCs in the recipient tissue, rendering them more resistant to the hostile microenvironment (cell-preconditioning). Another strategy aims at making the damaged tissue more receptive to the transplanted cells, favoring their interactions (tissue-preconditioning). In this review, we summarize several approaches using these strategies, providing an integral and updated view of the recent developments in MSC-based therapies. In addition, we propose that the combined use of these different conditioning strategies could accelerate the process to translate experimental evidences from pre-clinic studies to the daily clinical practice.

Adelie Penguins Pygoscelis adeliae live exclusively in Antarctica and commute between the sea for foraging and the land for breeding. During these movements, they must navigate various environments: underwater, on sea ice and on land; an unusual set of challenges among animals. Navigation mechanisms of this species were intensively studied about 50 years ago, but technological limitation at that time made it hard to fully understand movement patterns under experimental as well as natural conditions. Recent developments in animal-borne data loggers have enabled us to record movement paths and activities of such birds. In this paper, we report the results of displacement experiments combined with bio-logging on Adelie Penguins, conducted for the first time since initial experiments more than 50 years ago. Two chick rearing birds were caught at their nests and data loggers with GPS and accelerometers were deployed on their backs. The birds were artificially displaced and released approximately 1 km from the breeding colony. From the release point, their options to return to the nest were either walking over land or swimming in the sea. The birds successfully returned to the colony 6.0 h and 8.1 h after release, taking 44 min and 41 min, respectively, from the onset of homeward movement. Both individuals took what appeared to be the straightest and shortest course crossing over land. They spent most of the homing phase (51.2% and 66.2%) walking and only entered the water – in the same place – in the last stretch homewards. The results of our study demonstrate the homing ability of Adelie Penguins from a distant location after artificial displacement and the potential use of positional and acceleration data to study the navigation of penguins that travel by both land and sea.

Background Bone marrow is an important source of stem cells, which can promote bone fracture healing. Methods We investigated the optimal time to inject bone marrow mesenchymal stem cells (BMSCs) in a C57 murine unilateral, transverse, femur fracture model. BMSCs transfected with red fluorescent protein (RFP-BMSCs) were injected via the tail vein on day 1, 7, or 14 post-fracture. AMD3100 (inhibitor of stromal cell-derived factor 1 [SDF-1]) was also injected before RFP-BMSCs in one group for comparison; a control group received saline injections. RFP-BMSC migration and fracture healing were evaluated by in vivo fluorescence assay. Micro-CT was performed and mechanical testing and histological analysis. Chemokine levels were evaluated by quantitative real-time PCR and western blotting. Results Following injection on day 7 post-fracture, RFP-BMSCs more frequently homed to the fracture site and remained for a longer duration. Bone volume and bone mineral density were increased when BMSCs were injected on day 7 post-fracture (P

International audience; Innate lymphoid cells (ILCs) are immune cells that lack specific antigen receptors but possess similar effector functions as T cells. Concordantly, ILCs express many transcription factors known to be important for T cell effector function. ILCs develop from lymphoid progenitors in fetal liver and adult bone marrow. However, the identification of ILC progenitor (ILCP) and other precursors in peripheral tissues raises the question of whether ILC development might occur at extramedullary sites. We discuss central and local generation in maintaining ILC abundance at peripheral sites.

International audience; In this study, a desert ant-inspired celestial compass and a bio-inspired minimalist optic flow sensor named M 2 APix (which stands for Michaelis Menten Auto-adaptive Pixels), were embedded onboard our 2kg-hexapod walking robot called AntBot, in order to reproduce the homing behavior observed in desert ants Cataglyphis fortis. The robotic challenge here was to make the robot come back home autonomously after being displaced from its initial location. The navigation toolkit of AntBot comprises the celestial-based heading direction, and both stride-and ventral optic flow-based odometry, as observed in desert ants. Experimental results show that our bio-inspired approach can be useful for autonomous outdoor navigation robotics in case of GPS or magnetome-ter failure, but also to compensate for a drift of the inertial measurement unit. In addition, our strategy requires few computational resources due to the small number of pixels (only 14 here), and a high robustness and precision (mean error of 4.8cm for an overall path ranging from 2m to 5m). Finally, this work presents highly interesting field results of ant-based theoretical models for homing tasks that have not been tested yet in insectoid robots.

Habitat selection is a critical process for animals throughout their life, and adult organisms that travel to forage or mate must reselect habitat frequently. On coral reefs, competition for space has led to a high proportion of habitat specialists. Habitat selection is especially vital for organisms that require specialized habitat; however, research has primarily focused on the initial habitat choice made during the larval/juvenile stage. Here, we analyze habitat selection in the adult sponge-dwelling reef shrimp, Lysmata pederseni. Using a mark-and-recapture technique, belt transects, patch reefs, and cue isolation experiments, this study reveals that adult L. pederseni diurnally reselect habitat and a natural preference exists for specific sponge species and shapes. This natural preference is a function of chemical and morphological cues as well as sponge distribution. As habitat specialists can drive biodiversity, understanding the mechanisms behind habitat selection can inform research and management practices., Is architecture more important than smell when choosing a home? Here, we investigate the external cues involved in habitat selection of a sponge-associated shrimp after nightly forays on the reef. By tracking shrimp locations through time and isolating environmental variables, we conclude that while both sponge shape and chemical cues play a role in habitat selection, shape may be a more critical factor for resident shrimp.

CXCR4 was the first receptor identified for CXCL12, but a second receptor, CXCR7, has also been described and its function in hematopoietic cells remains unknown. By inhibition of CXCR4 and/or CXCR7, we showed that CXCR7 participates in normal CD34+ and U937 cell migration and prevents downregulation of CXCR4 by CXCL12 stimulation. In addition, CXCR7 contributes to homing of acute myeloid leukemia and normal progenitor cells to the bone marrow and spleen of NOD/SCID mice. In summary, this study shows an essential role of CXCR7, together with CXCR4, in the control of normal and malignant hematopoietic cell migration and homing induced by CXCL12.