Tuning Cell Motility via Cell Tension with a Mechanochemical Cell Migration Model

Cell migration is orchestrated by a complicated mechanochemical system. However, few cell migration models take into account the coupling between the biochemical network and mechanical factors. Here, we construct a mechanochemical cell migration model to study the cell tension effect on cell migration. Our model incorporates the interactions between Rac-GTP, Rac-GDP, F-actin, myosin, and cell tension, and it is very convenient in capturing the change of cell shape by taking the phase field approach. This model captures the characteristic features of cell polarization, cell shape change, and cell migration modes. It shows that cell tension inhibits migration ability monotonically when cells are applied with persistent external stimuli. On the other hand, if random internal noise is significant, the regulation of cell tension exerts a nonmonotonic effect on cell migration. Because the increase of cell tension hinders the formation of multiple protrusions, migration ability could be maximized at intermediate cell tension under random internal noise. These model predictions are consistent with our single-cell experiments and other experimental results.     

Role of the sympathetic nervous system in the pathogenesis of experimental glaucoma

It has been shown in experiments on rabbits that alpha-and beta-adrenoblockers, and lithium chloride solution exert different effect on intraocular tension of healthy animals with experimental glaucoma and transitory hypertension. The beta-blockker obsidan decreases the tension in experimental glaucoma. Pretreatment with the drug prevents the development of glaucoma. On the contrary, the alpha-blocker pirroxan promotes the development of glaucoma and does not elicit any hypotensive therapeutic effect. The drug-induced decrease in intraocular tension was recorded in healthy animals and in rabbits with transitory hypertensin of the eye. The hypotensive effect of lithium was noted only in the animals with experimental glaucoma. The role of alpha-and beta-adrenergic receiption in the pathogenesis of glaucoma is discussed.     

The peripheral nerve allograft in the primate immunosuppressed with Cyclosporin A: II. Functional evaluation of reinnervated muscle.

Isometric contractile function was evaluated in primates receiving peripheral nerve allografts and autografts. Twelve adult male cynomolgus monkeys received both sural nerve allografts and autografts to the ulnar nerve in opposite forearms. Half the animals received Cyclosporin A (CsA) immunosuppression (25 mg/kg per day); the remaining animals received placebo. One year following nerve engraftment, isometric contractile muscle function was evaluated in reinnervated abductor digiti quinti and intact abductor pollicis brevis muscles. Maximal twitch tension (Pt), tetanic tension (P(o)), time to peak tension (tpt), rate of rise of twitch tension (DP/dt), and muscle fatigue were evaluated at optimal muscle length (L(o)). All reinnervated muscles distal to nerve autografts and allografts in both Cyclosporin A-immunosuppressed and placebo-treated animals generated equivalent maximal twitch tension, tetanic tension, and time to peak tension, with no significant difference between groups (p > 0.05 by ANOVA). There was a tendency toward increased muscle fatiguability in Cyclosporin A-treated animals (p > 0.05). However, the rate of rise of twitch tension was significantly faster in the reinnervated and intact muscles of Cyclosporin A-treated primates (p < 0.05). Evidence of excellent functional reinnervation across nerve allografts and autografts similar to that seen in histologic and electrophysiologic studies was noted. Cyclosporin A immunosuppression did not significantly enhance recovery of muscle function distal to nerve allografts in this model.     

Hypoxic regulation of mesenchymal stem cell migration: the role of RhoA and HIF-1α

A variety of pathologies such as skeletal fracture, neoplasia and inflammation compromise tissue perfusion and thereby decrease tissue oxygen tension. We and others have demonstrated that hypoxia is a potent stimulant for MSC (mesenchymal stem cell) recruitment and differentiation, yet to date little research has focused on the effects of oxygen tension on MSC migration. In the present study, we examined the effects of hypoxia and the potential role of the GTPase RhoA and HIF-1α (hypoxia-inducible factor 1α) on MSC migration. Our results demonstrate that hypoxia decreases MSC migration through an HIF-1α and RhoA-mediated pathway. The active GTP-bound form of RhoA was reduced in 1% oxygen, whereas activation of RhoA under hypoxic conditions rescued migration. Furthermore, stabilization of HIF-1α under normoxic conditions attenuated cell migration similar to that of hypoxia. These results suggest that hypoxia negatively affects MSC migration by regulating activation of GTPases. These results highlight the importance of oxygen in regulating the recruitment of progenitor cells to areas of ischaemic tissue damage.     

Contractile properties of expiratory abdominal muscles: effect of elastase-induced emphysema

The present study examined the intrinsic contractile properties and endurance of the transverse abdominis and external oblique abdominal expiratory muscles in adult hamsters and compared their performance with the diaphragm. Experiments were performed in vitro on isolated bundles of muscle stimulated electrically. In control animals peak twitch tension was similar in the two muscles. In contrast, the twitch contraction time and one-half relaxation time of the transverse abdominis were significantly greater than that of the external oblique. The isometric tension generated over a range of stimulus frequencies (i.e., the force-frequency relationship) was a greater percent of the maximum value in response to subtetanizing frequencies (10-40 Hz) in the transverse abdominis than in the external oblique. For both abdominal muscles, however, the tension generated over this range of stimulus frequencies was less than that of the diaphragm. The endurance of the transverse abdominis during repeated contractions was significantly greater than that of the external oblique but similar to the diaphragm. The effect of chronic hyperinflation produced by elastase-induced emphysema on the contractile function of the two muscles was assessed in a second group of adult hamsters. In emphysematous animals peak twitch tension, contraction time, and one-half relaxation time of the twitch and force-frequency curves of muscles from emphysematous animals were similar to values obtained in control animals for both the external oblique and transverse abdominis. However, the endurance of both the transverse abdominis and external oblique muscles was greater in emphysematous than control animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

The migration of bone marrow cells to thymic culture supernatants is inhibited by stress

The effect of immobilization stress on precursor cell migration from bone marrow to the thymus was studied in C57BL/6 mice. The in vitro migration assays, using Nuclepore chambers, showed that precursor cell migration to thymus supernatants was strongly inhibited in stressed animals. This inhibition of migration seemed to be cell-associated what can explain the thymic involution observed in mice under stress conditions. The migration of precursor cells from bone marrow may be one of the mechanisms by which the thymus gland is involuted by stress.     

Pro-inflammatory effect of Arum maculatum lectin and role of resident cells

Arum maculatum agglutinin (AMA) is a monocot lectin isolated from tubers of Arum maculatum L. (Araceae) which exhibits different specificity towards oligo-mannosidic-type and N-acetyllactosaminic-type glycans. We have investigated the effect of this lectin on the cells of the immune system. Models of neutrophil migration in vivo, neutrophil chemotaxis in vitro and macrophage cultures were used to study the lectin inflammatory activity. When administered into rat peritoneal cavities, AMA (80, 200 and 500 microg/mL/cavity) induced significant and dose-dependent neutrophil migration. This effect was inhibited by incubation with alpha-methyl-d-mannoside. A 83% depletion in the number of resident cells following peritoneal lavage did not reduce the AMA-induced neutrophil migration, as compared to sham animals (not washed). However, pre-treatment with 3% thioglycolate which increases the peritoneal macrophage population by 236%, enhanced the neutrophil migration induced by AMA (200 microg/mL/cavity) (119%, p < 0.05). Reduction of peritoneal mast cell population by chronic treatment of cavities with compound 48/80 did not modify AMA-induced neutrophil migration. The neutrophil chemotaxy assay in vitro shows that the lectin (300 microg/mL) induces neutrophil chemotaxy (368% p < 0.05) compared to RPMI. Finally, injection into peritoneal cavities of supernatants from macrophage cultures obtained after stimulation with AMA (300 microg/mL) enhanced neutrophil migration (110% p < 0.05). Summarizing, our data suggest that A. maculatum agglutinin presents pro-inflammatory activity, inducing neutrophil migration by two ways, one which is independent on resident cells and another one dependent on the presence of these cells.     

Effect of Mechanical Forces on the Behavior of Dental Stem Cells: A Scoping Review of <i>In-Vitro</i> Studies

This article is a scoping review of the studies that assessed the effect of mechanical forces on the behavior of dental stem cells (DSCs). PubMed and Scopus searches were done for in-vitro studies evaluating the effect of tension, hydrostatic pressure (i.e., the pressure applied through an incompressible fluid), compression, simulated microgravity, and vibration on DSCs. The following factors were analyzed: osteogenic/odontogenic differentiation, proliferation, adhesion and migration. Articles were reviewed according to the Preferred Reporting Items for Systematic Reviews extension for scoping reviews (PRISMA-ScR) guideline. Included studies were evaluated based on the modified Consolidated Standards of Reporting Trials (CONSORT). A total of 18 studies published from 2008–2019 were included. Nine studies were focusing on Periodontal ligament Stem Cells (PDLSCs), eight studies on Dental Pulp Stem Cells (DPSCs) and one study on Stem Cells from Apical Papilla (SCAP). Results showed that tension, three-dimensional stress and simulated microgravity promoted the proliferation and osteogenic differentiation of PDLSCs. DPSCs proliferation increased after microgravity and tension exertion. In addition, dynamic hydrostatic pressure and compression promoted odontogenic differentiation of DPSCs. Besides, mechanical stimuli increased the osteogenic differentiation of DPSCs. One study analyzed the effect of carrier features on the response of DSCs to 3D-stress and showed that cells cultivated on scaffolds with 30% bioactive glass (BAG) had the highest osteogenic differentiation compared to other ratios of BAG. It has been shown that increasing the duration of tension (i.e., from 3 h to 24 h force application) enhanced the positive effect of force application on the osteogenic differentiation of DSCs. In conclusion, all types of mechanical forces except uniaxial tension increased the osteogenic/odontogenic differentiation of DSCs. In addition, the effect of mechanical stimulation on the proliferation of DSCs differs based on the type of stem cells and mechanical force.     

Are Baby Animals Less Appetizing? Tenderness toward Baby Animals and Appetite for Meat

Three studies investigated whether thoughts and feelings generated by baby animals might oppose appetite for meat. A prestudy established babyness as an important factor predicting moral concern for farmed animals. Study 1 showed that presenting images of baby animals, versus adult animals, as the source of meat reduced appetite for meat, but this effect was weak and found exclusively among women. Study 2 replicated and extended study 1 using a larger sample and two new animal sources. Study 3 included a no animal comparison condition, and found greatest levels of reduced appetite for meat when the meat source was presented as a baby animal, as opposed to an adult animal or with no visual indication of the animal source. A meta-analysis of the results using Bayes factors revealed considerable cumulative evidence in favor of the hypothesis that images of baby animals temporarily reduce women’s appetite for meat. In contrast, the evidence for men was less strong. Our results highlight a tension within some omnivores between caring for baby animals and appetite for meat.     

Effect of vinblastine on the cell cycle and migration of ameloblasts of mouse incisors as shown by autoradiography using 3H-thymidine

The effects of vinblastine on the cell cycle and the migration of ameloblasts were studied in the lower incisors of mice by labelling the cells with 3H-thymidine ([3H]TdR) and radioautography. A group of mice received 2 micrograms/g of body weight vinblastine intraperitoneally and 6 hr after these animals and those of a control group were injected with 1 microCi/g body weight of [3H]TdR, and sacrificed at time intervals from 0.75 hr to 15 days. The generation time of ameloblasts in the progenitor compartment was 14.8 hr in animals treated with vinblastine and 17 hr in the controls, using the FLM curve method; with the grain dilution method the duration was respectively 29.25 hr and 25.96 hr. The thymidine labelling index of the treated animals was 50% higher than the controls. The velocity of ameloblast migration, determined either by the displacement of the most incisally labelled cell or by the grain dilution method, was lower in the experimental group (2.48 cell positions/hr and 9.18 microns/hr respectively) as compared with the control (3.21 cell positions/hr and 18.88 microns/hr respectively). The results on the ameloblast production rate are contradictory but the slowing down in the velocity of cell migration is compatible with a decrease of the rate of cell production in the progenitor compartment as a vinblastine effect.     

Length-tension relationship of abdominal expiratory muscles: effect of emphysema

The present study examined the active and passive length-tension relationship of the abdominal expiratory muscles in vitro during electrically stimulated contractions. Studies were performed on isolated strips of transverse abdominis and external oblique muscle from nine adult hamsters with normal lung function. The effect of chronic hyperinflation on the two muscles was assessed in eight hamsters with elastase-induced emphysema. In normal animals the maximal active tension per cross-sectional area (Po) was equal in the two muscles. The absolute muscle fiber length at which Po occurred (Lo) was less for the external oblique than the transverse abdominis and the length-tension curve operated at shorter fiber lengths. However, the change in tension produced by an increase or decrease in muscle length expressed in relative terms (i.e., as %Lo) was greater for the transverse abdominis than the external oblique. Mean total lung capacity of emphysematous animals was 198% of control. Po of the transverse abdominis and external oblique were the same in emphysematous and control animals. However, Lo and the length-tension curve of the transverse abdominis occurred at shorter fiber lengths in emphysematous animals because of a reduction in the number of sarcomeres in series along the fiber. The length-tension curve and the number of sarcomeres in the external oblique was the same in emphysematous and control animals. These results in normal animals indicate that the magnitude of the change in active and passive tension produced by a change in muscle length differs in the transverse abdominis and external oblique. Moreover, chronic hyperinflation of the thorax produced by elastase injection alters the length-tension relationships of some but not all the expiratory muscles.     

Hypoxia-Induced Changes in the Bioactivity of Cytotrophoblast-Derived Exosomes

Migration of extravillous trophoblasts (EVT) into decidua and myometrium is a critical process in the conversion of maternal spiral arterioles and establishing placenta perfusion. EVT migration is affected by cell-to-cell communication and oxygen tension. While the release of exosomes from placental cells has been identified as a significant pathway in materno-fetal communication, the role of placental-derived exosomes in placentation has yet to be established. The aim of this study was to establish the effect of oxygen tension on the release and bioactivity of cytotrophoblast (CT)-derived exosomes on EVT invasion and proliferation. CT were isolated from first trimester fetal tissue (n = 12) using a trypsin-deoxyribonuclease-dispase/Percoll method. CT were cultured under 8%, 3% or 1% O2 for 48 h. Exosomes from CT-conditioned media were isolated by differential and buoyant density centrifugation. The effect of oxygen tension on exosome release (µg exosomal protein/10⁶cells/48 h) and bioactivity were established. HTR-8/SVneo (EVT) were used as target cells to establish the effect (bioactivity) of exosomes on invasion and proliferation as assessed by real-time, live-cell imaging (Incucyte™). The release and bioactivity of CT-derived exosomes were inversely correlated with oxygen tension (p<0.001). Under low oxygen tensions (i.e. 1% O2), CT-derived exosomes promoted EVT invasion and proliferation. Proteomic analysis of exosomes identified oxygen-dependent changes in protein content. We propose that in response to changes in oxygen tension, CTs modify the bioactivity of exosomes, thereby, regulating EVT phenotype. Exosomal induction of EVT migration may represent a normal process of placentation and/or an adaptive response to placental hypoxia.     

Endotoxin inhibits intestinal epithelial restitution through activation of Rho-GTPase and increased focal adhesions

Diseases of gut inflammation such as neonatal necrotizing enterocolitis (NEC) result after an injury to the mucosal lining of the intestine, leading to translocation of bacteria and endotoxin (lipopolysaccharide). Intestinal mucosal defects are repaired by the process of intestinal restitution, during which enterocytes migrate from healthy areas to sites of injury. In an animal model of NEC, we determined that intestinal restitution was significantly impaired compared with control animals. We therefore sought to determine the mechanisms governing enterocyte migration under basal conditions and after an endotoxin challenge. Here we show that the cytoskeletal reorganization and stress fiber formation required for migration in IEC-6 enterocytes requires RhoA. Enterocytes were found to express the endotoxin receptor Toll-like receptor 4, which served to bind and internalize lipopolysaccharide. Strikingly, endotoxin treatment significantly inhibited intestinal restitution, as measured by impaired IEC-6 cell migration across a scraped wound. Lipopolysaccharide was found to increase RhoA activity in a phosphatidylinositol 3-kinase-dependent manner, leading to an increase in phosphorylation of focal adhesion kinase and an enhanced number of focal adhesions. Importantly, endotoxin caused a progressive, RhoA-dependent increase in cell matrix tension/contractility, which correlated with the observed impairment in enterocyte migration. We therefore conclude that endotoxin inhibits enterocyte migration through a RhoA-dependent increase in focal adhesions and enhanced cell adhesiveness, which may participate in the impaired restitution observed in experimental NEC.     

Tracking the small with the smallest--using nanotechnology in tracking zooplankton

A major problem when studying behavior and migration of small organisms is that many of the questions addressed for larger animals are not possible to formulate due to constraints on tracking smaller animals. In aquatic ecosystems, this problem is particularly problematic for zoo- and phytoplankton, since tracking devices are too heavy to allow the organism to act naturally. However, recent advances in nanotechnology have made it possible to track individual animals and thereby to focus on important and urgent questions which previously have not been possible to address. Here we report on a novel approach to track movement and migratory behavior of millimeter sized aquatic animals, particularly Daphnia magna, using the commercially available nanometer sized fluorescent probes known as quantum dots. Experimental trials with and without quantum dots showed that they did not affect behavior, reproduction or mortality of the tested animals. Compared to previously used methods to label small animals, the nano-labeling method presented here offers considerable improvements including: 24 h fluorescence, studies in both light and darkness, much improved optical properties, potential to study large volumes and even track animals in semi-natural conditions. Hence, the suggested method, developed in close cooperation between biologists, chemists and physicists, offers new opportunities to routinely study zooplankton responses to light, food and predation, opening up advancements within research areas such as diel vertical/horizontal migration, partial migration and other differences in intra- and interspecific movements and migration.     

Migration dynamics for the ideal free distribution

This article verifies that the ideal free distribution (IFD) is evolutionarily stable, provided the payoff in each patch decreases with an increasing number of individuals. General frequency-dependent models of migratory dynamics that differ in the degree of animal omniscience are then developed. These models do not exclude migration at the IFD where balanced dispersal emerges. It is shown that the population distribution converges to the IFD even when animals are nonideal (i.e., they do not know the quality of all patches). In particular, the IFD emerges when animals never migrate from patches with a higher payoff to patches with a lower payoff and when some animals always migrate to the best patch. It is shown that some random migration does not necessarily lead to undermatching, provided migration occurs at the IFD. The effect of population dynamics on the IFD (and vice versa) is analyzed. Without any migration, it is shown that population dynamics alone drive the population distribution to the IFD. If animal migration tends (for each fixed population size) to the IFD, then the combined migration-population dynamics evolve to the population IFD independent of the two timescales (i.e., behavioral vs. population).     

Effect of Vinblastine On the Cell Cycle and Migration of Ameloblasts of Mouse Incisors As Shown By Autoradiography Using 3H-Thymidine

Abstract. The effects of vinblastine on the cell cycle and the migration of ameloblasts were studied in the lower incisors of mice by labelling the cells with ³H-thymidine ([³H]TdR) and radioautography. A group of mice received 2 μg/g of body weight vinblastine intraperitoneally and 6 hr after these animals and those of a control group were injected with 1μCi/g body weight of [³H]TdR, and sacrificed at time intervals from 0.75 hr to 15 days.
The generation time of ameloblasts in the progenitor compartment was 14.8 hr in animals treated with vinblastine and 17 hr in the controls, using the FLM curve method; with the grain dilution method the duration was respectively 29.25 hr and 25.96 hr. the thymidine labelling index of the treated animals was 50% higher than the controls. the velocity of ameloblast migration, determined either by the displacement of the most incisally labelled cell or by the grain dilution method, was lower in the experimental group (2.48 cell positions/hr and 9.18 μ/hr respectively) as compared with the control (3.21 cell positions/hr and 18.88 μm/hr respectively).
The results on the ameloblast production rate are contradictory but the slowing down in the velocity of cell migration is compatible with a decrease of the rate of cell production in the progenitor compartment as a vinblastine effect.     

Membrane tension maintains cell polarity by confining signals to the leading edge during neutrophil migration

Little is known about how neutrophils and other cells establish a single zone of actin assembly during migration. A widespread assumption is that the leading edge prevents formation of additional fronts by generating long-range diffusible inhibitors or by sequestering essential polarity components. We use morphological perturbations, cell-severing experiments, and computational simulations to show that diffusion-based mechanisms are not sufficient for long-range inhibition by the pseudopod. Instead, plasma membrane tension could serve as a long-range inhibitor in neutrophils. We find that membrane tension doubles during leading-edge protrusion, and increasing tension is sufficient for long-range inhibition of actin assembly and Rac activation. Furthermore, reducing membrane tension causes uniform actin assembly. We suggest that tension, rather than diffusible molecules generated or sequestered at the leading edge, is the dominant source of long-range inhibition that constrains the spread of the existing front and prevents the formation of secondary fronts.     

Unusual tension reception in an insect

Muscle tension receptors in animals monitor the tension generated by muscles. This information is important for the initiation and control of movements and for muscle tone in relation to spatial orientation and gravity. Vertebrates have tendon organs located at the musculo-tendinous junction. The number of muscle fibers attached to one receptor is in the range of 3 to 25. In insects by contrast, only a few examples are known where muscle tension is measured by only single receptors embedded in the muscle. All other muscle activity is monitored by a range of other receptors that detect strains on the cuticle or movements of the joints. Here we describe a set of approximately 200 receptor cells located on a single insect muscle. These receptor cells are associated with ovipositor muscle fibers and were preferentially responsive to muscle tension and not muscle length. Although single receptors may respond differently, their summed response to altered muscle tension characterized them as phasic-tonic type receptors. Experimental activation of muscle receptors in animals producing a basic oviposition motor pattern inhibited homonymous muscle activity without resetting the phase of the rhythm. These results suggest a potential role of tension receptors in regulating ovipositor muscle activity and in particular preventing excessive muscle tension during oviposition. The muscle receptors presented here provide the first example of tension measurement in insects by a few hundred receptor cells associated with a single muscle. Their role in motor control and relation to other tension receptors in vertebrates and invertebrates are discussed.     

Heat shock treatment results in increased recruitment of labeled PMN following myocardial infarction

One of the proposed mechanisms for the myocardial protective effects of heat shock (HS) treatment has been a reduction in the inflammatory response. The objective of the present study was to evaluate the impact of HS treatment in an established model of polymorphonuclear cell (PMN) migration following myocardial infarction (MI). Isolated purified PMNs (10 x 10(6) cells) labeled with (51)Cr were injected into Lewis rats following a left thoracotomy and ligation of the left anterior descending coronary artery causing MI. Two experimental groups of animals were created: MI group (n = 11) and HS+MI group (n = 7). HS treatment consisted of an elevation in core temperature to 42 degrees C for 15 min 24 h prior to MI. An additional group of control animals underwent sham thoracotomy (n = 5). All animals were euthanized at 24 h after MI, and gamma counts were obtained to estimate PMN migration. Myocardial injury was confirmed in all experimental animals (histology and echocardiography). The serum troponin I and infarct size (triphenyltetrazolium chloride) were similar in both groups. Labeled PMN migration was significantly higher in HS+MI animals (14.3 x 10(4) +/- 3.7 x 10(4) PMN) compared with MI group (9.5 x 10(4) +/- 3.6 x 10(4); P = 0.01), suggesting increased PMN migration as a result of HS treatment. HS treatment did not affect PMN migration to positive skin control sites (LPS). ICAM-1 myocardial expression was not significantly increased in HS+MI compared with MI group. In summary, HS treatment results in increased PMN migration into myocardium following MI independent of ICAM-1. These findings suggest that the proposed cardioprotective effect of HS may not be entirely due to a downregulation of myocardial inflammation as previously proposed.     

The Effect of Multipotent Mesenchymal Stromal Cell Derivatives on the Properties of Breast Cancer Cells in vitro and in vivo

The effects of multipotent mesenchymal stromal cell (MMSC) derivatives on breast cancer cells have been studied in vitro and in vivo. A cytostatic effect of substances produced by human bone marrow MMSCs on the tumor cell population and the inhibition of tumor cell migration into the suspension fraction in vitro were demonstrated. These phenomena were accompanied by upregulation of tumor-associated marker expression: cytokeratin and EpCAM expression was upregulated in 2D and 3D cell cultures and vimentin expression was upregulated in 3D cultures. A single injection of mouse bone marrow MMSC lysate into the experimental animals suppressed tumor growth in thigh muscles. Moreover, this treatment contributed to the preservation of muscle tissue integrity and the normalization of biochemical parameters of the blood in animals that received grafts of Ehrlich adenocarcinoma tumor cells.