How Do Mesenchymal Stromal Cells Suppress T Cells?

Accumulating information indicates that mesenchymal stem or stromal cells (MSCs) are immunomodulatory, but the data to explain the observations are frequently conflicting. In this issue of Cell Stem Cell, Ren et al. (2008) provide evidence for a possible underlying mechanism of MSC-mediated T cell suppression. A perspective for considering these interesting observations is discussed.     

Determining to Divide: How Do Cells Decide?

A cell's decision to divide must be regulated with the highest fidelity. Otherwise, abnormalities occurring in the replication of genetic material and cytokinesis would be incompatible with life. It has been known for almost a century that cells comprising a population undergo cellular division at extremely variable rates, even though genetically identical cell clones have been examined. Studies with T lymphocytes at the single cell level have revealed that the rate of cellular division is determined by the accumulation of a critical number of ligand-triggered interleukin-2 (IL2) receptors at the cell surface throughout the G₁ phase of the cell cycle. Thus, the cell “counts” the number of triggered IL2 receptors, and only decides to divide when the critical number has been attained. This information is then transferred to the cellular interior via intracellular sensors comprised of D-type cyclins, which ultimately determine when the cell surpasses the “Restriction Point” in late G₁, and which commits the cell irrevocably to initiate DNA replication. Beyond the R-point, the cell assembles a definite number of macromolecular pre-replication complexes (Pre-RCs) comprised of at least 6 distinct proteins at sites of the origin of replication on DNA. Complete assembly of the Pre-RCs is a prerequisite for their subsequent disassembly, which must occur before the initiation of DNA strand replication, and which occurs asynchronously throughout the S-phase of the cell cycle and only terminates when the entire DNA has been duplicated. Thus, the fidelity of the decision to divide is exquisitely regulated by macromolecular mechanisms initiated at the cell surface and transferred to the cellular interior so that the cell can make the decision in a quantal (all-or-none) fashion. The question before us is how this quantal decision is made at the molecular level. The available data indicate that the assembly and disassembly of a definite number of large multicomponent macromolecular complexes make the quantal decisions. Here, it is postulated that all fundamental cellular decisions, i.e. survival, death, proliferation and differentiation, are regulated in this fashion. It remains to be determined how the cell counts the signals it receives, and what the molecular forces are that dictate the behavior of macromolecular complexes. Alexander Hamilton: “The best security for the fidelity of men, is to make interest coincide with duty.”     

Why and How Do Plant Cells Sense Sugars?

The ability to sense sugars is crucial for the modulation ofgene expression in plants. Despite the importance of this phenomenon,our knowledge of sugar sensing in plants is scant. Several valuablehypotheses have been put forward based on the extensive knowledgeof sugar sensing in yeast. In recent years, tests of these hypotheseshave shown that hexokinase and sucrose-non-fermenting- (SNF-)related proteins appear to be involved in sugar sensing andtransduction, not only in yeast but also in higher plants. However,even if plants share with yeast some elements involved in sugarsensing, several aspects of sugar perception are likely to bepeculiar to higher plants. Plants should be able to sense notonly glucose but also other hexoses, such as fructose and disaccharides(sucrose, maltose and others). In this Botanical Briefing weoutline recent discoveries in this field, with emphasis on arabidopsisand cereals. The use of transgenic plants and mutants to identifysugar sensor(s) and elements in the signalling pathways andtheir cross-talk with the hormonal signalling is discussed.Copyright2001 Annals of Botany Company Abscisic acid, Arabidopsis thaliana, cereals, hexokinase, sugar sensing     

Childhood Obesity: Do Parents Recognize This Health Risk?

Objective: This study examined parents’ understanding of excess weight as a health risk, knowledge of healthy eating habits, and recognition of obesity in their children. Research Methods and Procedures: An anonymous questionnaire was distributed during well‐care visits involving children 4 to 8 years of age at a pediatric faculty practice. Parents indicated their level of concern about excess weight and other familiar health risks using a four‐point Likert scale, answered multiple‐choice questions concerning healthy eating patterns, and communicated their perceptions about their child's weight using a visual analog scale. A parent's perception was considered “accurate” if it deviated from the child's growth chart percentile by <30 points. Results: Of the 83 parents surveyed, 23% (19/83) had overweight children (≥95th percentile of age‐ and gender‐specific BMI growth charts). These parents did not differ from other parents in their level of concern about excess weight as a health risk or in their knowledge of healthy eating patterns, but the two groups of parents did differ in the accuracy of their perceptions about their children's weight. Only 10.5% of parents of overweight children (2/19) perceived their child's weight accurately compared with 59.4% of other parents (38/64; p < 0.001). Parents of overweight children invariably underestimated their children's weight. The median difference between their perception and the growth chart percentile was ?45 points. Discussion: Given that most parents of overweight children fail to recognize that their child has a weight problem, pediatricians should develop strategies to help these parents correct their misperceptions.     

How Do Filamentous Pathogens Deliver Effector Proteins into Plant Cells?

Fungal and oomycete plant parasites are among the most devastating pathogens of food crops. These microbes secrete effector proteins inside plant cells to manipulate host processes and facilitate colonization. How these effectors reach the host cytoplasm remains an unclear and debated area of plant research. In this article, we examine recent conflicting findings that have generated discussion in the field. We also highlight promising approaches based on studies of both parasite and host during infection. Ultimately, this knowledge may inform future broad spectrum strategies for protecting crops from such pathogens.     

Do Pioneer Cells Exist?

Most mathematical models of collective cell spreading make the standard assumption that the cell diffusivity and cell proliferation rate are constants that do not vary across the cell population. Here we present a combined experimental and mathematical modeling study which aims to investigate how differences in the cell diffusivity and cell proliferation rate amongst a population of cells can impact the collective behavior of the population. We present data from a three-dimensional transwell migration assay that suggests that the cell diffusivity of some groups of cells within the population can be as much as three times higher than the cell diffusivity of other groups of cells within the population. Using this information, we explore the consequences of explicitly representing this variability in a mathematical model of a scratch assay where we treat the total population of cells as two, possibly distinct, subpopulations. Our results show that when we make the standard assumption that all cells within the population behave identically we observe the formation of moving fronts of cells where both subpopulations are well-mixed and indistinguishable. In contrast, when we consider the same system where the two subpopulations are distinct, we observe a very different outcome where the spreading population becomes spatially organized with the more motile subpopulation dominating at the leading edge while the less motile subpopulation is practically absent from the leading edge. These modeling predictions are consistent with previous experimental observations and suggest that standard mathematical approaches, where we treat the cell diffusivity and cell proliferation rate as constants, might not be appropriate.     

Cell Penetrating Peptides: How Do They Do It?

Cell penetrating peptides consist of short sequences of amino acids containing a large net positive charge that are able to penetrate almost any cell, carrying with them relatively large cargoes such as proteins, oligonucleotides, and drugs. During the 10 years since their discovery, the question of how they manage to translocate across the membrane has remained unanswered. The main discussion has been centered on whether they follow an energy-independent or an energy-dependent pathway. Recently, we have discovered the possibility of an energy-independent pathway that challenges fundamental concepts associated with protein-membrane interactions (Herce and Garcia, PNAS, 104: 20805 (2007) [1]). It involves the translocation of charged residues across the hydrophobic core of the membrane and the passive diffusion of these highly charged peptides across the membrane through the formation of aqueous toroidal pores. The aim of this review is to discuss the details of the mechanism and interpret some experimental results consistent with this view.     

Foxp3+ Regulatory T Cells among Tuberculosis Patients: Impact on Prognosis and Restoration of Antigen Specific IFN-γ Producing T Cells

CD4⁺CD25⁺Foxp3⁺ Regulatory T cells (Treg) and programmed death-1 (PD-1) molecules have emerged as pivotal players in immune suppression of chronic diseases. However, their impact on the disease severity, therapeutic response and restoration of immune response in human tuberculosis remains unclear. Here, we describe the possible role of Treg cells, their M. tuberculosis driven expansion and contribution of PD-1 pathway to the suppressive function of Treg cells among pulmonary tuberculosis (PTB) patients. Multicolor flow cytometry, cell culture, cells sorting and ELISA were employed to execute the study. Our results showed significant increase in frequency of antigen-reactive Treg cells, which gradually declined during successful therapy and paralleled with decline of M. tuberculosis–specific IL-10 along with elevation of IFN-γ production, and raising the IFN-γ/IL-4 ratio. Interestingly, persistence of Treg cells tightly correlated with MDR tuberculosis. Also, we show that blocking PD-1/PD-L1 pathway abrogates Treg-mediated suppression, suggesting that the PD-1/PD-L1 pathway is required for Treg-mediated suppression of the antigen-specific T cells. Treg cells possibly play a role in dampening the effector immune response and abrogating PD-1 pathway on Treg cells significantly rescued protective T cell response, suggesting its importance in immune restoration among tuberculosis patients.     

Do Cells let-7 Determine Stemness?

During oncogenic transformation, microRNA levels of the translation-regulatory factor let-7 correlate inversely with expression of the HMGA2 oncoprotein. In a recent issue of Cell, Yu et al. (2007) now provide evidence that the let-7/HMGA2 linkage could be a signature of cancer stem cells in vivo, with broader implications for stem cell research.     

How Cells Protect Themselves against Stress?

The current evidence on the mechanisms underlying cell response to heat shock is reviewed. The response dynamics, induction, and attenuation as well as heat shock proteins and the mechanisms through which they protect cells from stress are considered. The role of these proteins in regulating the signaling cascades, including apoptosis suppression, is shown.     

How Do Rituals Affect Cooperation?

Collective rituals have long puzzled anthropologists, yet little is known about how rituals affect participants. Our study investigated the effects of nine naturally occurring rituals on prosociality. We operationalized prosociality as (1) attitudes about fellow ritual participants and (2) decisions in a public goods game. The nine rituals varied in levels of synchrony and levels of sacred attribution. We found that rituals with synchronous body movements were more likely to enhance prosocial attitudes. We also found that rituals judged to be sacred were associated with the largest contributions in the public goods game. Path analysis favored a model in which sacred values mediate the effects of synchronous movements on prosocial behaviors. Our analysis offers the first quantitative evidence for the long-standing anthropological conjecture that rituals orchestrate body motions and sacred values to support prosociality. Our analysis, moreover, adds precision to this old conjecture with evidence of a specific mechanism: ritual synchrony increases perceptions of oneness with others, which increases sacred values to intensify prosocial behaviors.