Development of approaches to improve the regenerative potential of muscle stem cells

Stem cell therapy is a promising treatment for diseases such as Duchenne muscular dystrophy (DMD) and ischemic heart failure. However, low survival and differentiation of transplanted cells hinders therapy. In this study, we examined ways to enhance the effectiveness of muscle cells for cardiomyoplasty by increasing antioxidant levels, explored the role of vascular endothelial growth factor (VEGF) in mechanical stimulation pre-treatment and characterized muscle derived stem cells (MDSCs) from normal and dystrophic mice. First we demonstrated that increasing antioxidant levels positively correlated with the early survival of myoblasts after implantation into infarcted hearts, but did not result in long term functional benefits, indicating that early survival does not necessarily correlate with long term regeneration and repair. Next we aimed to determine the effect of VEGF on mechanically stimulated MDSCs transplanted into dystrophic muscle. MDSCs were transduced with vectors carrying the LacZ reporter gene (lacZ-MDSCs), the soluble VEGF receptor Flt1 (sFlt1-MDSCs) or short hairpin RNA targeting VEGF messenger RNA (shRNA_VEGF MDSCs). They were subjected to 24 hours of cyclic strain and injected into the gastrocnemius muscles of dystrophic mdx/SCID mice. After 2 weeks, there was an increase in angiogenesis in muscles transplanted with mechanically stimulated lacZ-MDSCs compared to non-stimulated lacZ-MDSCs and sFlt1-MDSCs. Dystrophin positive myofiber regeneration and in vitro myotube differentiation were significantly lower in the shRNA_VEGF-MDSC group compared to the lacZ-MDSC and sFlt1-MDSC groups. Thus, the beneficial effects of mechanical stimulation on MDSC mediated muscle repair were lost by inhibiting VEGF. Finally, we aimed to compare wild-type (wt) MDSCs with MDSCs obtained from mdx and dystrophin/utrophin double knock out (DKO) mice, which are models of muscular dystrophy. We demonstrated that wt and mdx MDSCs did not have differences in proliferation, differentiation, or VEGF secretion. We compared DKO homozygous MDSCs and DKO heterozygous MDSCs and found that DKO homo MDSCs had decreased proliferation, differentiation, and cell survival capabilities compared to DKO het MDSCs. Finally, we pre-treated DKO MDSCs with mechanical stimulation and increased their proliferation rates. In conclusion, efforts to optimize cell therapy are necessary to improve transplantation outcomes for both ischemic cardiac repair and muscular diseases

The role of antioxidation and immunomodulation in postnatal multipotent stem cell-mediated cardiac repair

Oxidative stress and inflammation play major roles in the pathogenesis of coronary heart disease including myocardial infarction (MI). The pathological progression following MI is very complex and involves a number of cell populations including cells localized within the heart, as well as cells recruited from the circulation and other tissues that participate in inflammatory and reparative processes. These cells, with their secretory factors, have pleiotropic effects that depend on the stage of inflammation and regeneration. Excessive inflammation leads to enlargement of the infarction site, pathological remodeling and eventually, heart dysfunction. Stem cell therapy represents a unique and innovative approach to ameliorate oxidative stress and inflammation caused by ischemic heart disease. Consequently, it is crucial to understand the crosstalk between stem cells and other cells involved in post-MI cardiac tissue repair, especially immune cells, in order to harness the beneficial effects of the immune response following MI and further improve stem cell-mediated cardiac regeneration. This paper reviews the recent findings on the role of antioxidation and immunomodulation in postnatal multipotent stem cell-mediated cardiac repair following ischemic heart disease, particularly acute MI and focuses specifically on mesenchymal, muscle and blood-vessel-derived stem cells due to their antioxidant and immunomodulatory properties

The Antiferroelectric ↔ Ferroelectric Phase Transition in Lead-Containing and Lead-Free Perovskite Ceramics

A comprehensive review on the latest development of the antiferroelectric ferroelectric phase transition is presented. The abrupt volume expansion and sudden development of polarization at the phase transition has been extensively investigated in PbZrO3-based perovskite ceramics. New research developments in these compositions, including the incommensurate domain structure, the auxetic behavior under electric fields in the induced ferroelectric phase, the ferroelastic behavior of the multicell cubic phase, the impact of radial compression, the unexpected electric field-induced ferroelectric-to-antiferroelectric transition, and the phase transition mechanical toughening effect have been summarized. Due to their significance to lead-free piezoelectric ceramics, compounds with antiferroelectric phases, including NaNbO3, AgNbO3, and (Bi1/2Na1/2)TiO3, are also critically reviewed. Focus has been placed on the (Bi1/2Na1/2)TiO3–BaTiO3 solid solution where the electric field-induced ferroelectric phase remains even after the applied field is removed at room temperature. Therefore, the electric field-induced antiferroelectric-to-ferroelectric phase transition is a key to the poling process to develop piezoelectricity in morphotropic phase boundary (MPB) compositions. The competing phase transition and domain switching processes in 0.93(Bi1/2Na1/2)TiO3–0.07BaTiO3 are directly imaged with nanometer resolution using the unique in situ transmission electron microscopy (TEM) technique

Ultrahigh-Temperature Ceramics

Ultrahigh temperature ceramics (UHTCs) are a class of materials that include the diborides of metals such as hafnium and zirconium. The materials are of interest to NASA for their potential utility as sharp leading edges for hypersonic vehicles. Such an application requires that the materials be capable of operating at temperatures, often in excess of 2,000 C. UHTCs are highly refractory and have high thermal conductivity, an advantage for this application. UHTCs are potentially applicable for other high-temperature processing applications, such as crucibles for molten-metal processing and high-temperature electrodes. UHTCs were first studied in the 1960 s by the U.S. Air Force. NASA s Ames Research Center concentrated on developing materials in the HfB2/SiC family for a leading-edge application. The work focused on developing a process to make uniform monolithic (2-phase) materials, and on the testing and design of these materials. Figure 1 shows arc-jet models made from UHTC materials fabricated at Ames. Figure 2 shows a cone being tested in the arc-jet. Other variations of these materials being investigated elsewhere include zirconium based materials and fiber-reinforced composites. Current UHTC work at Ames covers four broad topics: monoliths, coatings, composites, and processing. The goals include improving the fracture toughness, thermal conductivity and oxidation resistance of monolithic UHTCs and developing oxidation-resistant UHTC coatings for thermal-protection-system substrates through novel coating methods. As part of this effort, researchers are exploring compositions and processing changes that have yielded improvements in properties. Computational materials science and nanotechnology are being explored as approaches to reduce materials development time and improve and tailor properties

Mechanical loading of stem cells for improvement of transplantation outcome in a model of acute myocardial infarction: The role of loading history

Stem cell therapy for tissue repair is a rapidly evolving field and the factors that dictate the physiological responsiveness of stem cells remain under intense investigation. In this study we hypothesized that the mechanical loading history of muscle-derived stem cells (MDSCs) would significantly impact MDSC survival, host tissue angiogenesis, and myocardial function after MDSC transplantation into acutely infarcted myocardium. Mice with acute myocardial infarction by permanent left coronary artery ligation were injected with either nonstimulated (NS) or mechanically stimulated (MS) MDSCs. Mechanical stimulation consisted of stretching the cells with equibiaxial stretch with a magnitude of 10% and frequency of 0.5Hz. MS cell-transplanted hearts showed improved cardiac contractility, increased numbers of host CD31+ cells, and decreased fibrosis, in the peri-infarct region, compared to the hearts treated with NS MDSCs. MS MDSCs displayed higher vascular endothelial growth factor expression than NS cells in vitro. These findings highlight an important role for cyclic mechanical loading preconditioning of donor MDSCs in optimizing MDSC transplantation for myocardial repair. © 2012, Mary Ann Liebert, Inc

Mechanical loading of stem cells for improvement of transplantation outcome in a model of acute myocardial infarction: the role of loading history

Stem cell therapy for tissue repair is a rapidly evolving field and the factors that dictate the physiological responsiveness of stem cells remain under intense investigation. In this study we hypothesized that the mechanical loading history of muscle-derived stem cells (MDSCs) would significantly impact MDSC survival, host tissue angiogenesis, and myocardial function after MDSC transplantation into acutely infarcted myocardium. Mice with acute myocardial infarction by permanent left coronary artery ligation were injected with either nonstimulated (NS) or mechanically stimulated (MS) MDSCs. Mechanical stimulation consisted of stretching the cells with equibiaxial stretch with a magnitude of 10% and frequency of 0.5 Hz. MS cell-transplanted hearts showed improved cardiac contractility, increased numbers of host CD31 + cells, and decreased fibrosis, in the peri-infarct region, compared to the hearts treated with NS MDSCs. MS MDSCs displayed higher vascular endothelial growth factor expression than NS cells in vitro. These findings highlight an important role for cyclic mechanical loading preconditioning of donor MDSCs in optimizing MDSC transplantation for myocardial repair

Biomechanical analyses of the performance of Paralympians: From foundation to elite level

Biomechanical analysis of sport performance provides an objective method of determining performance of a particular sporting technique. In particular, it aims to add to the understanding of the mechanisms influencing performance, characterization of athletes, and provide insights into injury predisposition. Whilst the performance in sport of able-bodied athletes is well recognised in the literature, less information and understanding is known on the complexity, constraints and demands placed on the body of an individual with a disability. This paper provides a dialogue that outlines scientific issues of performance analysis of multi-level athletes with a disability, including Paralympians. Four integrated themes are explored the first of which focuses on how biomechanics can contribute to the understanding of sport performance in athletes with a disability and how it may be used as an evidence-based tool. This latter point questions the potential for a possible cultural shift led by emergence of user-friendly instruments. The second theme briefly discusses the role of reliability of sport performance and addresses the debate of two-dimensional and three-dimensional analysis. The third theme address key biomechanical parameters and provides guidance to clinicians, and coaches on the approaches adopted using biomechanical/sport performance analysis for an athlete with a disability starting out, to the emerging and elite Paralympian. For completeness of this discourse, the final theme is based on the controversial issues on the role of assisted devices and the inclusion of Paralympians into able-bodied sport is also presented. All combined, this dialogue highlights the intricate relationship between biomechanics and training of individuals with a disability. Furthermore, it illustrates the complexity of modern training of athletes which can only lead to a better appreciation of the performances to be delivered in the London 2012 Paralympic Games

Enhanced tonic GABAA inhibition in typical absence epilepsy

The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired GABAergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABAA receptor–dependent ‘tonic’ inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake by the GABA transporter GAT–1 in the genetic models tested, and GAT–1 is critical in governing seizure genesis. Extrasynaptic GABAA receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABAA receptors is sufficient to elicit both electrographic and behavioural correlates of seizures in normal animals. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic significance, and highlight novel therapeutic targets for the treatment of absence epilepsy.peer-reviewe