Hepatocyte growth factor (HGF), a pleiotropic cytokine of mesenchymal origin promoting migration, proliferation, and survival in a wide spectrum of cells, can also modulate different biological responses in stem cells, but the mechanisms involved are not completely understood so far. In this context, we show that short-term exposure of mesenchymal stem cells (MSCs) to HGF can induce the activation of its cognate Met receptor and the downstream effectors ERK1/2, p38MAPK, and PI3K/Akt, while long-term exposure to HGF resulted in cytoskeletal rearrangement, cell migration, and marked inhibition of proliferation through the arrest in the G 1 -S checkpoint.When added to MSCs, the K252A tyrosine kinase inhibitor prevented HGF-induced responses. HGF's effect on MSC proliferation was reversed by p38 inhibitor SB203580, while the effects on cell migration were abrogated by PI3K inhibitor Wortmannin, suggesting that HGF acts through different pathways to determine its complex effects on MSCs. Prolonged treatment with HGF induced the expression of cardiac-specific markers (GATA-4, MEF2C, TEF1, desmin, ␣-MHC, ␤-MHC, and nestin) with the concomitant loss of the stem cell markers nucleostemin, c-kit, and CD105. STEM CELLS 2006;24: 23-33

In less than a decade the levels of performance of microbial fuel cells (MFCs) in terms of current output, voltage, and power density have grown tremendously according to steady exponential trends. Achievements occurred over the past 2-3 years have been particularly impressive. This is due partly to a better understanding of the biological aspects of this multidisciplinary technology, but also to systematic work undertaken by several research groups worldwide aimed at improving and optimizing aspects related to materials and system configuration. Aim of this review is to outline the current perspective about MFCs by focusing on the recent major advances in the areas of materials and engineering. MFCs are promising devices to address sustainability concerns both in terrestrial and space applications.

Cardiac progenitor cells (CPCs) are a promising autologous source of cells for cardiac\ud regenerative medicine. However, CPC culture in vitro requires the presence of microenvironmental\ud conditions (a complex array of bioactive substance concentration, mechanostructural\ud factors, and physicochemical factors) closely mimicking the natural cell surrounding in vivo,\ud including the capability to uphold reactive oxygen species (ROS) within physiological levels\ud in vitro. Cerium oxide nanoparticles (nanoceria) are redox-active and could represent a potent\ud tool to control the oxidative stress in isolated CPCs. Here, we report that 24 h exposure to 5, 10,\ud and 50 !g/mL of nanoceria did not a!ect cell growth and function in cardiac progenitor cells,\ud while being able to protect CPCs from H2O2-induced cytotoxicity for at least 7 days, indicating\ud that nanoceria in an e!ective antioxidant. Therefore, these "ndings con"rm the great\ud potential of nanoceria for controlling ROS-induced cell damage

a b s t r a c tA novel (scalable) electrospinning process was developed to fabricate bio-inspired multiscale threedimensional scaffolds endowed with a controlled multimodal distribution of fiber diameters and geared towards soft tissue engineering. The resulting materials finely mingle nano-and microscale fibers together, rather than simply juxtaposing them, as is commonly found in the literature. A detailed proof of concept study was conducted on a simpler bimodal poly(e-caprolactone) (PCL) scaffold with modes of fiber distribution at 600 nm and 3.3 lm. Three conventional unimodal scaffolds with mean diameters of 300 nm and 2.6 and 5.2 lm, respectively, were used as controls to evaluate the new materials. Characterization of the microstructure (i.e. porosity, fiber distribution and pore structure) and mechanical properties (i.e. stiffness, strength and failure mode) indicated that the multimodal scaffold had superior mechanical properties (Young's modulus $40 MPa and strength $1 MPa) in comparison with the controls, despite the large porosity ($90% on average). A biological assessment was conducted with bone marrow stromal cell type (mesenchymal stem cells, mTERT-MSCs). While the new material compared favorably with the controls with respect to cell viability (on the outer surface), it outperformed them in terms of cell colonization within the scaffold. The latter result, which could neither be practically achieved in the controls nor expected based on current models of pore size distribution, demonstrated the greater openness of the pore structure of the bimodal material, which remarkably did not come at the expense of its mechanical properties. Furthermore, nanofibers were seen to form a nanoweb bridging across neighboring microfibers, which boosted cell motility and survival. Lastly, standard adipogenic and osteogenic differentiation tests served to demonstrate that the new scaffold did not hinder the multilineage potential of stem cells.

Hybrid 2D polymeric–ceramic biosupports are fabricated by mixing a nanostructured CeO2 powder with 85:15 poly(D,L‐lactic‐co‐glycolic acid) (PLGA)/dichloromethane solutions at specific concentrations, followed by solvent casting onto pre‐patterned molds. The mold patterning allows the orientation of ceramic nanoparticles into parallel lines within the composite scaffold. The ability of the produced films to host and address cell growth is evaluated after 1, 3, and 6 days of culturing with murine derived cardiac and mesenchymal stem cells (CSCs and MSCs), and compared with PLGA films without ceramics and loaded with nanostructured TiO2. Aligned cell growth is observed only for scaffolds that incorporate oriented ceramic nanoparticles, attributed to the nanoceramic ability to modulate the roughness pitch, thus improving cell sensitivity towards the host surface features. Better CSC and MSC proliferative activity is observed for CeO2 composites with respect to either TiO2‐added or unfilled PLGA films. This evidence may be related to the nanostructured CeO2 antioxidative properties.

The replacement of injured cardiac contractile cells with stem cell-derived functionally efficient cardiomyocytes has been envisaged as the resolutive treatment for degenerative heart diseases. Nevertheless, many technical issues concerning the optimal procedures to differentiate and engraft stem cells remain to be answered before heart cell therapy could be routinely used in clinical practice. So far, most studies have been focused on evaluating the differentiative potential of different growth factors without considering that only the synergistic cooperation of biochemical, topographic, chemical, and physical factors could induce stem cells to adopt the desired phenotype. The present study demonstrates that the differentiation of cardiac progenitor cells to cardiomyocytes does not occur when cells are challenged with soluble growth factors alone, but requires strictly controlled procedures for the isolation of a progenitor cell population and the artifactual recreation of a microenvironment critically featured by a fine-tuned combination of specific biological and physical factors. Indeed, the scaffold geometry and stiffness are crucial in enhancing growth factor differentiative effects on progenitor cells. The exploitation of this concept could be essential in setting up suitable procedures to fabricate functionally efficient engineered tissues.

T he Hippo pathway has been recently identified as a crucial axis in the regulation of organ size and shape during organogenesis and cancer. The paralog Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1 or TAZ) are the downstream effectors of the Hippo pathway. These proteins have also been identified as mammalian proto-oncogenes. 1 Moreover, they perform as transcriptional coactivators in the nucleus, mainly in combination with transcription factors belonging to TEAD family. 2 In vitro, YAP/TAZ activity has been associated with mesenchymal stem cell (MSC) fate decision through the interaction with key determinants of osteogenic (Runx2) or adipogenic (PPARγ) differentiation. 3,4 YAP/TAZ axis has also emerged as a central regulator of human embryonic stem cell self-renewal through the control of SMAD complex shuttling to the nucleus, with TAZ knock-down resulting in the loss of cell pluripotency. 5 The same cofactors control intestinal 6 and neural progenitor cell number and differentiation 7 by targeting We identify a novel activity of YAP and TAZ in the regulation of tubulogenesis in 3D environments and highlight a role for YAP/TAZ in cardiac progenitor proliferation and differentiation. Furthermore, we show that YAP/TAZ expression is triggered in the heart cells located at the infarct border zone. Our results suggest a fundamental role for the YAP/TAZ axis in the response of resident progenitor cells to the modifications in microenvironment nanostructure and mechanics, thereby contributing to the maintenance of myocardial homeostasis in the adult heart. These proteins are indicated as potential targets to control cardiac progenitor cell fate by materials design.

Natural antimicrobial peptides represent a primordial mechanism of immunity in both vertebrate and nonvertebrate organisms. Among them, histatins belong to a family of human salivary metal-binding peptides displaying potent antibacterial, antifungal and wound-healing activities. These properties, along with the ability of histatins to inhibit collagenases and cysteine proteases, have attracted much attention for their potential use in the treatment of several oral diseases. This review critically assesses the studies carried out to date in order to provide a comprehensive and systematic vision of the information accumulated so far. In particular, the relationship between metal-binding and peptide activity is extensively analysed. The review provides important clues for developing possible therapeutic applications of histatins and their synthetic peptide analogues by creating a set of necessary resource materials to support investigators and industries interested in exploiting their unique properties.