Intravenous and intramyocardial injection of apoptotic white blood cell suspensions prevents ventricular remodelling by increasing elastin expression in cardiac scar tissue after myocardial infarction

Congestive heart failure developing after acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Clinical trials of cell-based therapy after AMI evidenced only a moderate benefit. We could show previously that suspensions of apoptotic peripheral blood mononuclear cells (PBMC) are able to reduce myocardial damage in a rat model of AMI. Here we experimentally examined the biochemical mechanisms involved in preventing ventricular remodelling and preserving cardiac function after AMI. Cell suspensions of apoptotic cells were injected intravenously or intramyocardially after experimental AMI induced by coronary artery ligation in rats. Administration of cell culture medium or viable PBMC served as controls. Immunohistological analysis was performed to analyse the cellular infiltrate in the ischaemic myocardium. Cardiac function was quantified by echocardiography. Planimetry of the infarcted hearts showed a significant reduction of infarction size and an improvement of post AMI remodelling in rats treated with suspensions of apoptotic PBMC (injected either intravenously or intramoycardially). Moreover, these hearts evidenced enhanced homing of macrophages and cells staining positive for c-kit, FLK-1, IGF-I and FGF-2 as compared to controls. A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells. Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue. The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling

Critical synchronization dynamics of the Kuramoto model on connectome and small world graphs

The hypothesis, that cortical dynamics operates near criticality also suggests, that it exhibits universal critical exponents which marks the Kuramoto equation, a fundamental model for synchronization, as a prime candidate for an underlying universal model. Here, we determined the synchronization behavior of this model by solving it numerically on a large, weighted human connectome network, containing 804092 nodes, in an assumed homeostatic state. Since this graph has a topological dimension $d < 4$, a real synchronization phase transition is not possible in the thermodynamic limit, still we could locate a transition between partially synchronized and desynchronized states. At this crossover point we observe power-law--tailed synchronization durations, with $\tau_t \simeq 1.2(1)$, away from experimental values for the brain. For comparison, on a large two-dimensional lattice, having additional random, long-range links, we obtain a mean-field value: $\tau_t \simeq 1.6(1)$. However, below the transition of the connectome we found global coupling control-parameter dependent exponents $1 < \tau_t \le 2$, overlapping with the range of human brain experiments. We also studied the effects of random flipping of a small portion of link weights, mimicking a network with inhibitory interactions, and found similar results. The control-parameter dependent exponent suggests extended dynamical criticality below the transition point.Comment: 12 pages, 9 figures + Supplemenraty material pdf 2 pages 4 figs, 1 table, accepted version in Scientific Report

Secretome of apoptotic peripheral blood cells (APOSEC) confers cytoprotection to cardiomyocytes and inhibits tissue remodelling after acute myocardial infarction: a preclinical study

Heart failure following acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Our previous observation that injection of apoptotic peripheral blood mononuclear cell (PBMC) suspensions was able to restore long-term cardiac function in a rat AMI model prompted us to study the effect of soluble factors derived from apoptotic PBMC on ventricular remodelling after AMI. Cell culture supernatants derived from irradiated apoptotic peripheral blood mononuclear cells (APOSEC) were collected and injected as a single dose intravenously after myocardial infarction in an experimental AMI rat model and in a porcine closed chest reperfused AMI model. Magnetic resonance imaging (MRI) and echocardiography were used to quantitate cardiac function. Analysis of soluble factors present in APOSEC was performed by enzyme-linked immunosorbent assay (ELISA) and activation of signalling cascades in human cardiomyocytes by APOSEC in vitro was studied by immunoblot analysis. Intravenous administration of a single dose of APOSEC resulted in a reduction of scar tissue formation in both AMI models. In the porcine reperfused AMI model, APOSEC led to higher values of ejection fraction (57.0 vs. 40.5%, p < 0.01), a better cardiac output (4.0 vs. 2.4 l/min, p < 0.001) and a reduced extent of infarction size (12.6 vs. 6.9%, p < 0.02) as determined by MRI. Exposure of primary human cardiac myocytes with APOSEC in vitro triggered the activation of pro-survival signalling-cascades (AKT, Erk1/2, CREB, c-Jun), increased anti-apoptotic gene products (Bcl-2, BAG1) and protected them from starvation-induced cell death. Intravenous infusion of culture supernatant of apoptotic PBMC attenuates myocardial remodelling in experimental AMI models. This effect is probably due to the activation of pro-survival signalling cascades in the affected cardiomyocytes

Diabetic Impairment of C-Kit+ Bone Marrow Stem Cells Involves the Disorders of Inflammatory Factors, Cell Adhesion and Extracellular Matrix Molecules

Bone marrow stem cells from diabetes mellitus patients exhibit functional impairment, but the relative molecular mechanisms responsible for this impairment are poorly understood. We investigated the mechanisms responsible for diabetes-related functional impairment of bone marrow stem cells by extensively screening the expression levels of inflammatory factors, cell cycle regulating molecules, extracellular matrix molecules and adhesion molecules. Bone marrow cells were collected from type 2 diabetic (db/db) and healthy control (db/m+) mice, and c-kit+ stem cells were purified (purity>85%) for experiments. Compared with the healthy control mice, diabetic mice had significantly fewer c-kit+ stem cells, and these cells had a lower potency of endothelial differentiation; however, the production of the angiogenic growth factor VEGF did not differ between groups. A pathway-focused array showed that the c-kit+ stem cells from diabetic mice had up-regulated expression levels of many inflammatory factors, including Tlr4, Cxcl9, Il9, Tgfb1, Il4, and Tnfsf5, but no obvious change in the expression levels of cell cycle molecules. Interestingly, diabetes-related alterations of the extracellular matrix and adhesion molecules were varied; Pecam, Mmp10, Lamc1, Itgb7, Mmp9, and Timp4 were up-regulated, but Col11a1, Fn1, Admts2, and Itgav were down-regulated. Some of these changes were also confirmed at the protein level by flow cytometry analysis. In conclusion, c-kit+ bone marrow stem cells from diabetic mice exhibited an extensive enhancement of inflammatory factors and disorders of the extracellular matrix and adhesion molecules. Further intervention studies are required to determine the precise role of each molecule in the diabetes-related functional impairment of c-kit+ bone marrow stem cells

Endothelial progenitor cells and integrins: adhesive needs

In the last decade there have been multiple studies concerning the contribution of endothelial progenitor cells (EPCs) to new vessel formation in different physiological and pathological settings. The process by which EPCs contribute to new vessel formation in adults is termed postnatal vasculogenesis and occurs via four inter-related steps. They must respond to chemoattractant signals and mobilize from the bone marrow to the peripheral blood; home in on sites of new vessel formation; invade and migrate at the same sites; and differentiate into mature endothelial cells (ECs) and/or regulate pre-existing ECs via paracrine or juxtacrine signals. During these four steps, EPCs interact with different physiological compartments, namely bone marrow, peripheral blood, blood vessels and homing tissues. The success of each step depends on the ability of EPCs to interact, adapt and respond to multiple molecular cues. The present review summarizes the interactions between integrins expressed by EPCs and their ligands: extracellular matrix components and cell surface proteins present at sites of postnatal vasculogenesis. The data summarized here indicate that integrins represent a major molecular determinant of EPC function, with different integrin subunits regulating different steps of EPC biology. Specifically, integrin α4β1 is a key regulator of EPC retention and/or mobilization from the bone marrow, while integrins α5β1, α6β1, αvβ3 and αvβ5 are major determinants of EPC homing, invasion, differentiation and paracrine factor production. β2 integrins are the major regulators of EPC transendothelial migration. The relevance of integrins in EPC biology is also demonstrated by many studies that use extracellular matrix-based scaffolds as a clinical tool to improve the vasculogenic functions of EPCs. We propose that targeted and tissue-specific manipulation of EPC integrin-mediated interactions may be crucial to further improve the usage of this cell population as a relevant clinical agent

Chaos and correlated avalanches in excitatory neural networks with synaptic plasticity

A collective chaotic phase with power law scaling of activity events is observed in a disordered mean field network of purely excitatory leaky integrate-and-fire neurons with short-term synaptic plasticity. The dynamical phase diagram exhibits two transitions from quasi-synchronous and asynchronous regimes to the nontrivial, collective, bursty regime with avalanches. In the homogeneous case without disorder, the system synchronizes and the bursty behavior is reflected into a doubling-period transition to chaos for a two dimensional discrete map. Numerical simulations show that the bursty chaotic phase with avalanches exhibits a spontaneous emergence of time correlations and enhanced Kolmogorov complexity. Our analysis reveals a mechanism for the generation of irregular avalanches that emerges from the combination of disorder and deterministic underlying chaotic dynamics.Comment: 5 pages 5 figures; SI 26 pages 14 figures. Improved editing, 3 subsections added in S

Critical branching processes in digital memcomputing machines

Memcomputing is a novel computing paradigm that employs time non-locality (memory) to solve combinatorial optimization problems. It can be realized in practice by means of non-linear dynamical systems whose point attractors represent the solutions of the original problem. It has been previously shown that during the solution search digital memcomputing machines go through a transient phase of avalanches (instantons) that promote dynamical long-range order. By employing mean-field arguments we predict that the distribution of the avalanche sizes follows a Borel distribution typical of critical branching processes with exponent $\tau= 3/2$. We corroborate this analysis by solving various random 3-SAT instances of the Boolean satisfiability problem. The numerical results indicate a power-law distribution with exponent $\tau = 1.51 \pm 0.02$, in very good agreement with the mean-field analysis. This indicates that memcomputing machines self-tune to a critical state in which avalanches are characterized by a branching process, and that this state persists across the majority of their evolution.Comment: 5 pages, 3 figure

Homeostatic plasticity and external input shape neural network dynamics

In vitro and in vivo spiking activity clearly differ. Whereas networks in vitro develop strong bursts separated by periods of very little spiking activity, in vivo cortical networks show continuous activity. This is puzzling considering that both networks presumably share similar single-neuron dynamics and plasticity rules. We propose that the defining difference between in vitro and in vivo dynamics is the strength of external input. In vitro, networks are virtually isolated, whereas in vivo every brain area receives continuous input. We analyze a model of spiking neurons in which the input strength, mediated by spike rate homeostasis, determines the characteristics of the dynamical state. In more detail, our analytical and numerical results on various network topologies show consistently that under increasing input, homeostatic plasticity generates distinct dynamic states, from bursting, to close-to-critical, reverberating and irregular states. This implies that the dynamic state of a neural network is not fixed but can readily adapt to the input strengths. Indeed, our results match experimental spike recordings in vitro and in vivo: the in vitro bursting behavior is consistent with a state generated by very low network input (< 0.1%), whereas in vivo activity suggests that on the order of 1% recorded spikes are input-driven, resulting in reverberating dynamics. Importantly, this predicts that one can abolish the ubiquitous bursts of in vitro preparations, and instead impose dynamics comparable to in vivo activity by exposing the system to weak long-term stimulation, thereby opening new paths to establish an in vivo-like assay in vitro for basic as well as neurological studies.Comment: 14 pages, 8 figures, accepted at Phys. Rev.

A Lloyd-model generalization: Conductance fluctuations in one-dimensional disordered systems

We perform a detailed numerical study of the conductance $G$ through one-dimensional (1D) tight-binding wires with on-site disorder. The random configurations of the on-site energies $\epsilon$ of the tight-binding Hamiltonian are characterized by long-tailed distributions: For large $\epsilon$, $P(\epsilon)\sim 1/\epsilon^{1+\alpha}$ with $\alpha\in(0,2)$. Our model serves as a generalization of 1D Lloyd's model, which corresponds to $\alpha=1$. First, we verify that the ensemble average $\left\langle -\ln G\right\rangle$ is proportional to the length of the wire $L$ for all values of $\alpha$, providing the localization length $\xi$ from $\left\langle-\ln G\right\rangle=2L/\xi$. Then, we show that the probability distribution function $P(G)$ is fully determined by the exponent $\alpha$ and $\left\langle-\ln G\right\rangle$. In contrast to 1D wires with standard white-noise disorder, our wire model exhibits bimodal distributions of the conductance with peaks at $G=0$ and $1$. In addition, we show that $P(\ln G)$ is proportional to $G^\beta$, for $G\to 0$, with $\beta\le\alpha/2$, in agreement to previous studies.Comment: 5 pages, 5 figure