Multiscale Analysis of Extracellular Matrix Remodeling in the Failing Heart.

RATIONALE: Cardiac ECM (extracellular matrix) comprises a dynamic molecular network providing structural support to heart tissue function. Understanding the impact of ECM remodeling on cardiac cells during heart failure (HF) is essential to prevent adverse ventricular remodeling and restore organ functionality in affected patients. OBJECTIVES: We aimed to (1) identify consistent modifications to cardiac ECM structure and mechanics that contribute to HF and (2) determine the underlying molecular mechanisms. METHODS AND RESULTS: We first performed decellularization of human and murine ECM (decellularized ECM) and then analyzed the pathological changes occurring in decellularized ECM during HF by atomic force microscopy, 2-photon microscopy, high-resolution 3-dimensional image analysis, and computational fluid dynamics simulation. We then performed molecular and functional assays in patient-derived cardiac fibroblasts based on YAP (yes-associated protein)-transcriptional enhanced associate domain (TEAD) mechanosensing activity and collagen contraction assays. The analysis of HF decellularized ECM resulting from ischemic or dilated cardiomyopathy, as well as from mouse infarcted tissue, identified a common pattern of modifications in their 3-dimensional topography. As compared with healthy heart, HF ECM exhibited aligned, flat, and compact fiber bundles, with reduced elasticity and organizational complexity. At the molecular level, RNA sequencing of HF cardiac fibroblasts highlighted the overrepresentation of dysregulated genes involved in ECM organization, or being connected to TGFß1 (transforming growth factor ß1), interleukin-1, TNF-α, and BDNF signaling pathways. Functional tests performed on HF cardiac fibroblasts pointed at mechanosensor YAP as a key player in ECM remodeling in the diseased heart via transcriptional activation of focal adhesion assembly. Finally, in vitro experiments clarified pathological cardiac ECM prevents cell homing, thus providing further hints to identify a possible window of action for cell therapy in cardiac diseases. CONCLUSIONS: Our multiparametric approach has highlighted repercussions of ECM remodeling on cell homing, cardiac fibroblast activation, and focal adhesion protein expression via hyperactivated YAP signaling during HF.

Controlled formation of fluorescent metalloporphyrin-containing coordination polymer particles from seed structures by designed shape-transformation reactions.

Herein, nanorod structures and four-leaf clover structures of fluorescent zinc 5,10,15,20-tetra(4-pyridyl)-21H,23H-porphine (ZnTPyP)-containing coordination polymer particles (CPPs) were first synthesized by a bottom-up strategy assisted by surfactants and then employed as seed structures for further shape-transformation reactions. We have successfully designed the morphological transformation for different dimensions, achieving the controlled formation of octahedron structures at both the nanometer scale and micrometer scale from the seed structures. Our approach illustrates a new method to design and synthesize metalloporphyrin-containing CPPs in a systematic and controllable manner.

TGF-ß induces matrisome pathological alterations and EMT in patient-derived prostate cancer tumoroids.

Extracellular matrix (ECM) tumorigenic alterations resulting in high matrix deposition and stiffening are hallmarks of adenocarcinomas and are collectively defined as desmoplasia. Here, we thoroughly analysed primary prostate cancer tissues obtained from numerous patients undergoing radical prostatectomy to highlight reproducible structural changes in the ECM leading to the loss of the glandular architecture. Starting from patient cells, we established prostate cancer tumoroids (PCTs) and demonstrated they require TGF-ß signalling pathway activity to preserve phenotypical and structural similarities with the tissue of origin. By modulating TGF-ß signalling pathway in PCTs, we unveiled its role in ECM accumulation and remodelling in prostate cancer. We also found that TGF-ß-induced ECM remodelling is responsible for the initiation of prostate cell epithelial-to-mesenchymal transition (EMT) and the acquisition of a migratory, invasive phenotype. Our findings highlight the cooperative role of TGF-ß signalling and ECM desmoplasia in prompting prostate cell EMT and promoting tumour progression and dissemination.

Versatile and Resistant Electroless Pore-Plated Pd-Membranes for H2-Separation: Morphology and Performance of Internal Layers in PSS Tubes.

Pd-membranes are interesting in multiple ultra-pure hydrogen production processes, although they can suffer inhibition by certain species or abrasion under fluidization conditions in membrane reactors, thus requiring additional protective layers to ensure long and stable operation. The ability to incorporate intermediate and palladium films with enough adherence on both external and internal surfaces of tubular porous supports becomes crucial to minimize their complexity and cost. This study addresses the incorporation of CeO2 and Pd films onto the internal side of PSS tubes for applications in which further protection could be required. The membranes so prepared, with a Pd-thickness around 12-15 µm, show an excellent mechanical resistance and similar performance to those prepared on the external surface. A good fit to Sieverts' law with an H2-permeance of 4.571 × 10-3 mol m-2 s-1 Pa-0.5 at 400 °C, activation energy around 15.031 kJ mol-1, and complete ideal perm-selectivity was observed. The permeate fluxes reached in H2 mixtures with N2, He, or CO2 decreased with dilution and temperature due to the inherent concentration-polarization. The presence of CO in mixtures provoked a higher decrease because of a further inhibition effect. However, the original flux was completely recovered after feeding again with pure hydrogen, maintaining stable operation for at least 1000 h.

Pd-Based Membranes: Overview and Perspectives.

Palladium (Pd)-based membranes have received a lot of attention from both academia and industry thanks to their ability to selectively separate hydrogen from gas streams. Integration of such membranes with appropriate catalysts in membrane reactors allows for hydrogen production with CO2 capture that can be applied in smaller bioenergy or combined heat and power (CHP) plants, as well as in large-scale power plants. Pd-based membranes are, therefore, regarded as a Key Enabling Technology (KET) to facilitate the transition towards a knowledge-based, low carbon and resource-efficient economy. This Special Issue of the journal Membranes on "Pd-based Membranes: Overview and Perspectives" contains nine peer-reviewed articles. Topics include manufacturing techniques, understanding of material phenomena, module and reactor design, novel applications, and demonstration efforts and industrial exploitation.

Thermodynamic Aspects in Non-Ideal Metal Membranes for Hydrogen Purification.

In this paper, an overview on thermodynamic aspects related to hydrogen-metal systems in non-ideal conditions is provided, aiming at systematically merging and analyzing information achieved from several different studies present in the open literature. In particular, the relationships among inner morphology, dissolved hydrogen and internal stresses are discussed in detail, putting in evidence the conformation complexity and the various types of dislocations induced by the presence of H-atoms in the lattice. Specifically, it is highlighted that the octahedral sites are preferentially occupied in the FCC metals (such as palladium), whereas tetrahedral sites are more energetically favored in BCC-structured ones (such as vanadium). These characteristics are shown to lead to a different macroscopic behavior of the two classes of metals, especially in terms of solubility and mechanical failure due to the consequent induced stresses. Furthermore, starting from the expression of the chemical potential generally presented in the literature, a new convenient expression of the activity of the H-atoms dissolved into the metal lattice as a function of the H-concentration is achieved. Such an activity expression is then used in the dissolution equilibrium relationship, which is shown to be the overall result of two different phenomena: (i) dissociative adsorption of molecular hydrogen onto the surface; and (ii) atomic hydrogen dissolution from the surface to the metal bulk. In this way, the obtained expression for equilibrium allows a method to calculate the equilibrium composition in non-ideal conditions (high pressure), which are of interest for real industrial applications.

Trace Detection of Metalloporphyrin-Based Coordination Polymer Particles via Modified Surface-Enhanced Raman Scattering Assisted by Surface Metallization.

This study proposed a facile method to detect metalloporphyrin-based coordination polymer particles (Z-CPPs) in aqueous solution by modified surface-enhanced Raman scattering (SERS). The SERS-active particles are photodeposited on the surface of Z-CPPs, offering an enhanced Raman signal for the trace detection of Z-CPPs.

Inhibition by CO and polarization in Pd-based membranes: a novel permeation reduction coefficient.

In this Article, a novel permeation reduction coefficient (PRC) is defined and used to take into account the presence of both inhibition by CO and concentration polarization in hydrogen permeation through Pd-based membranes. The usefulness of this coefficient consists in the possibility of describing simply, but at the same time powerfully, the behavior of the membrane subject to the combined effect of inhibition and polarization. According to this approach, the effective permeance, which is generally unknown because it depends on these two phenomena, can be directly evaluated by multiplying the "clean" intrinsic membrane Sieverts permeance (measurable by simple pure hydrogen permeation tests) by a PRC function, that is, [effective permeance] = (1-PRC) [clean Sieverts permeance]. The values of PRC are evaluated by means of a complex model that takes into account the several elementary permeation steps, in which the inhibitory effect of CO is also considered as well as the concentration polarization. The membrane behavior is evaluated in terms of some "performance maps", where PRC and other two coefficients (concentration polarization coefficient (CPC) and inhibition coefficient (IC)) are reported as functions of several operating conditions (hydrogen molar fraction, CO partial pressure, and upstream total pressures). Therefore, these maps provide a useful tool to estimate directly the main design parameter (the overall permeance) in situations where complex transport and kinetic phenomena affect the membrane performances, allowing the membrane performance to be estimated much better and the separation equipment to be better designed.

Sieverts law empirical exponent for Pd-based membranes: critical analysis in pure H2 permeation.

In this paper, the physical meaning of the Sieverts-type driving force exponent n is analyzed for hydrogen permeation through Pd-based membranes by considering a complex model involving several elementary permeation steps (adsorption on the membrane surface on the feed side, desorption from the surface on the permeate side, diffusion through the metal lattice, and the two transition phenomena surface-to-bulk and bulk-to-surface). First, the characteristic driving force of each step is evaluated, showing that adsorption and desorption singularly considered and the adsorption and desorption considered at the same time are characterized by driving forces depending on the ratio of feed and permeate hydrogen pressure. On the contrary, the diffusion step is found to present a driving force that is composed of two terms, one which corresponds to the original Sieverts law (with an exponent of 0.5) and the other which is the product of the pressure difference and a temperature-dependent factor. Then, the characteristic n is evaluated by applying the multistep model to two different membranes from the literature in several cases, (a) considering each permeation step as the only limiting one and (b) considering the overall effect of all steps. The results of the analysis show that for a low temperature and thin membrane thickness, the effect of the surface phenomena is, in general, a decrease of the overall exponent n toward values lower than 0.5, even though, under particular operating conditions, the n theoretical value of the surface phenomena is equal to unity. At a higher temperature and thickness (diffusion-controlled permeation), n tends to 0.5, even though the rapidity of this tendency depends strictly on the membrane diffusional parameters. In this frame, the expression developed for the diffusion step provides a theoretical reason why n values higher than 0.5 are found even for thick membranes and high temperature, where diffusion is the only rate-determining step.