Degree Of Functional Heterogeneity Research Articles

Glucose-dependent activation, activity, and deactivation of beta cell networks in acute mouse pancreas tissue slices.

Many details of glucose-stimulated intracellular calcium changes in β cells during activation, activity, and deactivation, as well as their concentration-dependence, remain to be analyzed. Classical physiological experiments indicated that in islets, functional differences between individual cells are largely attenuated, but recent findings suggest considerable intercellular heterogeneity, with some cells possibly coordinating the collective responses. To address the above with an emphasis on heterogeneity and describing the relations between classical physiological and functional network properties, we performed functional multicellular calcium imaging in mouse pancreas tissue slices over a wide range of glucose concentrations. During activation, delays to activation of cells and any-cell-to-first-responder delays are shortened, and the sizes of simultaneously responding clusters increased with increasing glucose concentrations. Exactly the opposite characterized deactivation. The frequency of fast calcium oscillations during activity increased with increasing glucose up to 12 mM glucose concentration, beyond which oscillation duration became longer, resulting in a homogenous increase in active time. In terms of functional connectivity, islets progressed from a very segregated network to a single large functional unit with increasing glucose concentration. A comparison between classical physiological and network parameters revealed that the first-responders during activation had longer active times during plateau and the most active cells during the plateau tended to deactivate later. Cells with the most functional connections tended to activate sooner, have longer active times, and deactivate later. Our findings provide a common ground for recent differing views on β cell heterogeneity and an important baseline for future studies of stimulus-secretion and intercellular coupling.NEW & NOTEWORTHY We assessed concentration-dependence in coupled β cells, degree of functional heterogeneity, and uncovered possible specialized subpopulations during the different phases of the response to glucose at the level of many individual cells. To this aim, we combined acute mouse pancreas tissue slices with functional multicellular calcium imaging over a wide range from threshold (7 mM) and physiological (8 and 9 mM) to supraphysiological (12 and 16 mM) glucose concentrations, classical physiological, and advanced network analyses.

Diversity and environmental adaptation of phagocytic cell metabolism.

Phagocytes are cells of the immune system that play important roles in phagocytosis, respiratory burst and degranulation—key components of innate immunity and response to infection. This diverse group of cells includes monocytes, macrophages, dendritic cells, neutrophils, eosinophils, and basophils—heterogeneous cell populations possessing cell and tissue‐specific functions of which cellular metabolism comprises a critical underpinning. Core functions of phagocytic cells are diverse and sensitive to alterations in environmental‐ and tissue‐specific nutrients and growth factors. As phagocytic cells adapt to these extracellular cues, cellular processes are altered and may contribute to pathogenesis. The considerable degree of functional heterogeneity among monocyte, neutrophil, and other phagocytic cell populations necessitates diverse metabolism. As we review our current understanding of metabolism in phagocytic cells, gaps are focused on to highlight the need for additional studies that hopefully enable improved cell‐based strategies for counteracting cancer and other diseases.

Abstract SY27-02: Heterogeneity of tumor-associated macrophages: Implications for antiangiogenic therapy

Abstract SY27-02: Heterogeneity of tumor-associated macrophages: Implications for antiangiogenic therapy

Functional heterogeneity of the atrial myocardium of patients with congenital and acquired heart defects

In experiments on atrium trabeculae the heterogeneity of myocardium contractile activity in patients operated on for inborn or acquired heart defects was studied. Contractile activity was assessed in isometric regime of muscle drugs work. The degree of functional heterogeneity was reported to differ in myocardium biopsies from patients with inborn or acquired heart defects. The difference was expressed in susceptibility to stimulating action or electrical impulses and in the degree of the change of myocardium contractile activity. The study of human myocardium functional heterogeneity is likely to present a new approach to increase efficacy of the work of pathologically changed heart muscle.

Heat-killed Listeria monocytogenes and L. monocytogenes soluble antigen induce clonable CD4+ T lymphocytes with protective and chemotactic activities in vivo

In the present study we attempted to analyze the possibility to induce in mice a T-cell response using killed Listeria monocytogenes in adjuvant. Clearly, nonviable antigen is capable of inducing protective and granuloma-forming T cells in C57BL/6 mice when emulsified in complete Freund's adjuvant. These T cells were cloned in vitro by using antigen and irradiated splenocytes, as antigen-presenting cells, and the clones were characterized in vivo. Listeria-specific T-cell clones showed protective and chemotactic activity upon adoptive transfer, although some degree of functional heterogeneity among different clones was observed. The heterogeneous in vivo functions could not be correlated with the ability of the clones to produce gamma interferon or T-cell growth factor (interleukin-2 and/or interleukin-4). It was demonstrated that an in vivo relevant fraction of listeria-specific T lymphocytes can be induced by nonviable antigen in complete Freund's adjuvant. These results show that the low immunogenicity of heat-killed bacteria is not due to the expression of specific protective T-cell epitopes only by live bacteria.

Suckling Increases the Proportions of Mammotropes Responsive to Various Prolactin-Releasing Stimuli*

It is well established that the suckling stimulus sensitizes or primes the anterior pituitary to PRL-releasing stimuli. It is also recognized that PRL-secreting cells from a given animal are not all alike but instead exhibit a considerable degree of functional heterogeneity. The goal of the present study was to determine whether the suckling-induced priming phenomenon is manifest at the cellular level by shifts in the relative abundance of various mammotrope subpopulations. This was accomplished by using reverse hemolytic plaque assays to evaluate the secretory characteristics of individual PRL secretors derived from lactating rats either before or after the transient application of a suckling stimulus. Groups of day 10 lactating rats separated from their litters for 4 h were either killed immediately or were reunited briefly (10 min) with their pups before death. Adenohypophyseal cells obtained after trypsin dispersion were then subjected to plaque assays for PRL. Mammotropes derived from suckled rats were, on average, considerably more responsive to the stimulatory actions of TRH and angiotensin II and less susceptible to inhibition by dopamine. Mammotropes from nonsuckled rats exhibited a bimodal frequency distribution in which plaques from the second mode were roughly 6-8 times larger (released considerably more PRL) than those from the first. Superimposition of suckling (or in vitro treatment with dopamine) caused the second mode to disappear. Suckling also enhanced greatly the fraction of PRL cells that shifted from the first to the second mode (i.e. released more hormone) after treatment with TRH or angiotensin II. Taken together, our results demonstrate that the suckling-induced sensitization of pituitary tissue to PRL-releasing stimuli is manifest at the cellular level as proportional shifts toward those cells most responsive to stimulatory secretagogues and away from those most susceptible to inhibition by dopamine.

Functional heterogeneity among cytotoxic clones derived from natural killer cells.

Clones were obtained from highly purified populations of human peripheral blood natural killer (NK) cells propagated in the presence of interleukin-2 and phytohaemagglutinin. Almost all clones were cytotoxic against standard NK targets and many were also able to kill the B lymphoblastoid cell line BSM. This latter property was not necessarily a result of the incorporation of this cell line into the feeder mixture used to derive the clones. In most cloning experiments there was a high degree of concordance between the killing of the NK targets K562 and Molt 4 by panels of clones. In some cases this extended to the killing of BSM targets but in other instances there was no relationship or even an inverse correlation between killing of BSM and other targets. In a single cloning experiment there was no relationship between killing of BSM and Raji targets. In some cases a panel of clones could be divided into two or more distinct groups based on their differential activity towards BSM and K562. Such differences were not solely due to inter-donor variation. These findings were extended by cold target inhibition experiments in which at least three types of clone were identified. In one group of clones, which was nonreactive towards BSM, cold BSM significantly enhanced the killing of K562 in a dose-dependent fashion. These experiments provide evidence for a limited degree of functional heterogeneity among clones derived from human peripheral blood NK cells.

A Bayesian Analysis of Capillary Heterogeneity in the Intact Pig Liver

Published experimental data on the steady elimination of galactose by five isolated perfused pig livers are interpreted in terms of a model of hepatic uptake, in which the functional properties of the individual liver capillaries (hepatic sinusoids) are not identical. Kinetic parameters, including the Michaelis constant for the local enzyme-substrate interaction, are determined for each preparation on the basis of this model and are compared with previously obtained values based on an earlier model in which the sinusoids were assumed to be functionally identical. Posterior distributions of the degree of functional heterogeneity and the value of the Michaelis constant are given for the case where the livers are considered as a statistically homogeneous group. The degree of functional heterogeneity of the capillaries is found to be consistent with previous independent estimates.