Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a debilitating fatal X-linked muscle disorder. Recent findings indicate that IGFs play a central role in skeletal muscle regeneration and development. Among IGFs, insulinlike growth factor 2 (IGF2) is a key regulator of cell growth, survival, migration and differentiation. The type 2 IGF receptor (IGF2R) modulates circulating and tissue levels of IGF2 by targeting it to lysosomes for degradation. We found that IGF2R and the store-operated Ca2+ channel CD20 share a common hydrophobic binding motif that stabilizes their association. Silencing CD20 decreased myoblast differentiation, whereas blockade of IGF2R increased proliferation and differentiation in myoblasts via the calmodulin/calcineurin/NFAT pathway. Remarkably, anti-IGF2R induced CD20 phosphorylation, leading to the activation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) and removal of intracellular Ca2+. Interestingly, we found that IGF2R expression was increased in dystrophic skeletal muscle of human DMD patients and mdx mice. Blockade of IGF2R by neutralizing antibodies stimulated muscle regeneration, induced force recovery and normalized capillary architecture in dystrophic mdx mice representing an encouraging starting point for the development of new biological therapies for DMD

Impaired Angiogenic Potential of Human Placental Mesenchymal Stromal Cells in Intrauterine Growth Restriction

Human placental mesenchymal stromal cells (pMSCs) have never been investigated in intrauterine growth restriction (IUGR). We characterized cells isolated from placental membranes and the basal disc of six IUGR and five physiological placentas. Cell viability and proliferation were assessed every 7 days during a 6-week culture. Expression of hematopoietic, stem, endothelial, and mesenchymal markers was evaluated by flow cytometry. We characterized the multipotency of pMSCs and the expression of genes involved in mitochondrial content and function. Cell viability was high in all samples, and proliferation rate was lower in IUGR compared with control cells. All samples presented a starting heterogeneous population, shifting during culture toward homogeneity for mesenchymal markers and occurring earlier in IUGR than in controls. In vitro multipotency of IUGR-derived pMSCs was restricted because their capacity for adipocyte differentiation was increased, whereas their ability to differentiate toward endothelial cell lineagewasdecreased. Mitochondrial content and function were higher in IUGR pMSCs than controls, possibly indicating a shift from anaerobic to aerobic metabolism, with the loss of the metabolic characteristics that are typical of undifferentiated multipotent cells

Improvement of endurance of DMD animal model using natural polyphenols

Duchenne Muscular Dystrophy (DMD), the most common form of muscular dystrophy, is characterized by muscular wasting caused by dystrophin deficiency that ultimately ends in force reduction and premature death. In addition to primary genetic defect, several mechanisms contribute to DMD pathogenesis. Recently, antioxidant supplementation was shown to be effective in the treatment of multiple diseases including muscular dystrophy. Different mechanisms were hypothesized such as reduced hydroxyl radicals, nuclear factor-\u3baB deactivation and NO protection from inactivation. Following these promising evidences, we investigated the effect of the administration of a mix of dietary natural polyphenols (ProAbe) on dystrophic mdx mice in term of muscular architecture and functionality. We observed a reduction of muscle fibrosis deposition and myofiber necrosis together with an amelioration of vascolarization. More importantly, the recovery of the morphological features of dystrophic muscle leads to an improvement of the endurance of treated dystrophic mice. Our data confirmed that ProAbe-based diet may represent a strategy to co-adjuvate the treatment of DMD

Temporal Comparison of PBDEs, OH-PBDEs, PCBs, and OH-PCBs in the Serum of Second Trimester Pregnant Women Recruited from San Francisco General Hospital, California

Prenatal exposures to polybrominated diphenyl ethers (PBDEs) can harm neurodevelopment in humans and animals. In 2003–2004, PentaBDE and OctaBDE were banned in California and phased-out of US production; resulting impacts on human exposures are unknown. We previously reported that median serum concentrations of PBDEs and their metabolites (OH-PBDEs) among second trimester pregnant women recruited from San Francisco General Hospital (2008–2009; n=25) were the highest among pregnant women worldwide. We recruited another cohort from the same clinic in 2011–2012 (n=36) and now compare serum concentrations of PBDEs, OH-PBDEs, polychlorinated biphenyl ethers (PCBs) (structurally similar compounds banned in 1979), and OH-PCBs between two demographically similar cohorts. Between 2008–2009 and 2011–2012, adjusted least square geometric mean (LSGM) concentrations of ΣPBDEs decreased 65% (95% CI: 18, 130) from 90.0 ng/g lipid (95% CI: 64.7,125.2) to 54.6 ng/g lipid (95% CI: 39.2, 76.2) (p=0.004); Σ OH-PBDEs decreased six-fold (p<0.0001); and BDE-47, -99, and -100 declined more than BDE-153. There was a modest, non-significant (p=0.13) decline in LSGM concentrations of ΣPCBs and minimal differences in ΣOH-PCBs between 2008–2009 and 2011–2012. PBDE exposures are likely declining due to regulatory action, but the relative stability in PCB exposures suggests PBDE exposures may eventually plateau and persist for decades

A Metal-Oxide-Semiconductor Varactor

CMOS technology scaling opens up the possibility of designing variable capacitors based on a metal oxide semiconductor structure with improved tuning range and quality factor. This is due to an increase in the oxide capacitance and a reduction in the parasitic resistance. A prototype metal-oxide-semiconductor (MOS) variable capacitor of 3.1 pF nominal value has been realized in a 0.35-μm standard CMOS process. A factor two capacitance change has been achieved for a 2-V variation of the controlling voltage. The varactor Q ranges from 17 to 35, at 1.8 GH

Cell Based Therapy for Duchenne Muscular Dystrophy

Mutations in the dystrophin gene cause an X-linked genetic disorder: Duchenne muscular dystrophy (DMD). Stem cell therapy is an attractive method to treat DMD because a small number of cells are required to obtain a therapeutic effect. Here, we discussed about multiple types of myogenic stem cells and their possible use to treat DMD. The identification of a stem cell population providing efficient muscle regeneration is critical for the progression of cell therapy for DMD. We speculated that the most promising possibility for the treatment of DMD is a combination of different approaches, such as gene and stem cell therapy

Combining multiple therapeutic strategies for Friedreich&#8217;s ataxia (FRDA): antioxidant metallic nanoclusters as coadjuvants for gene and stem cell therapy

Introduction FRDA pathology is caused by guanine\u2013adenine\u2013adenine trinucleotide repeat expansion within the first intron of frataxin (FTX) gene, leading to epigenetic silencing. Since mitochondrial FTX controls cellular iron use and redox status maintenance, its lack causes an increased level of reactive oxygen species. We report an effective lentivirus FXN gene delivery to FTX deficient mesenchymal stem cells (MSCs), inducing improvement of neurological functionalities when transplanted in vivo. We also identify antioxidant nanoclusters (NCs) able to block ROS\u2013dependent apoptotic pathways in the FRDA pathology. Methods MSCs from FRDA patient bone marrows were transduced with a lentiviral vector for FXN expression. After LV transduced MSC characterization by FACS, IF, and WB analyses, engineered cells were systemically injected in Fxntm1MknTg (FXN)YG8Pook/2J mice. Behaviour tests (rotarod and treadmill) were performed. Brain tissues were harvested for IF staining and WB. FRDA MSCs labelled with AuAg NCs were characterized to evaluate mitochondrial ROS scavenger activity. Results After LV transduction, MSCs showed the preservation of mesenchymal marker expression (CD73, CD44, CD90 and CD105), colony forming abilities, and capacity to differentiate into multilineages. Comparison with untreated animals revealed i) in vivo FTX rescue; ii) increased number of cerebellar cells expressing Tuj1 neuronal marker; and iii) improvement trend of motor skills in mice injected with engineered MSCs. In addiction, AuAg NCs entered the mitochondria of FRDA MSCs where they reduce ROS levels lowering cell sensitivity to oxidative stress. Conclusions The results confirm the gene and stem cells-based therapeutic applicability to treat the neuronal degeneration in FRDA. The suitability of metallic NCs as anti oxidant agents represents a crucial point as implemental strategy for further ameliorating the progressive ROS mediated degeneration. Indeed, a combined approach based on NCs nasal inhalation in autologous transplanted FRDA patients may be considered as a step further into a clinically relevant treatment

Clinical applications of mesenchymal stem cells in chronic diseases

Extraordinary progress in understanding several key features of stem cells has been made in the last ten years, including definition of the niche, and identification of signals regulating mobilization and homing as well as partial understanding of the mechanisms controlling self-renewal, commitment, and differentiation. This progress produced invaluable tools for the development of rational cell therapy protocols that have yielded positive results in preclinical models of genetic and acquired diseases and, in several cases, have entered clinical experimentation with positive outcome. Adult mesenchymal stem cells (MSCs) are nonhematopoietic cells with multilineage potential to differentiate into various tissues of mesodermal origin. They can be isolated from bone marrow and other tissues and have the capacity to extensively proliferate in vitro. Moreover, MSCs have also been shown to produce anti-inflammatory molecules which can modulate humoral and cellular immune responses. Considering their regenerative potential and immunoregulatory effect, MSC therapy is a promising tool in the treatment of degenerative, inflammatory, and autoimmune diseases. It is obvious that much work remains to be done to increase our knowledge of the mechanisms regulating development, homeostasis, and tissue repair and thus to provide new tools to implement the efficacy of cell therapy trials