The Structure and Function of Glial Networks: Beyond the Neuronal Connections.

Glial cells, consisting of astrocytes, oligodendrocyte lineage cells, and microglia, account for >50% of the total number of cells in the mammalian brain. They play key roles in the modulation of various brain activities under physiological and pathological conditions. Although the typical morphological features and characteristic functions of these cells are well described, the organization of interconnections of the different glial cell populations and their impact on the healthy and diseased brain is not completely understood.

Intestinal Dopamine Receptor D2 is Required for Neuroprotection Against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Dopaminergic Neurodegeneration.

A wealth of evidence has suggested that gastrointestinal dysfunction is associated with the onset and progression of Parkinson's disease (PD). However, the mechanisms underlying these links remain to be defined. Here, we investigated the impact of deregulation of intestinal dopamine D2 receptor (DRD2) signaling in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration.

Central dopaminergic control of cell proliferation in the colonic epithelium.

Parkinson's disease (PD) is an age-related neurodegenerative disease, mainly characterized by the loss of dopaminergic (DA) neurons in the substantia nigra. Several non-motor symptoms, including those associated with gastrointestinal dysfunction, precede the classical motor symptoms in PD. However, the mechanisms underlying gastrointestinal dysfunction in the prodromal phase of PD remain elusive.

Highly-efficient and easy separation of γ-FeO selectively adsorbs U(Ⅵ) in waters.

The migration and transformation of uranyl [U (Ⅵ)] ions in the environment are quite dependent on the geological condition in particular with the site enriched in Fe. In this study, the interfacial interaction of U (Ⅵ) ions with maghemite (γ-FeO) particles was studied and the interaction mechanism was explored as well. Batch experiments confirm that γ-FeO can effectively remove U (Ⅵ) from an aqueous solution within a relatively short reaction time (R% > 92.

Assessment of heavy metals mobility and correlative recovery and decontamination from MSWI fly ash: Mechanism and hydrometallurgical process evaluation.

Fly ash from municipal solid waste incineration (MSWI) enriches many leachable toxic metals which readily migrate into the environment, posing serious risks to the ecosystem and human. In this study, the elements mobility, leaching availability as well as the potential maximum amounts of heavy metals in fly ash were thoroughly evaluated. To decontaminate the toxic elements from resulting fly ash leachates, The aqueous zinc (Zn) was recovered using Cyanex 572, cadmium (Cd) and copper (Cu) were effectively removed through adsorption process by a self-assembled hierarchical hydroxyapatite (HAP) nanostructure.

Graphene oxide functionalized with nano hydroxyapatite for the efficient removal of U(VI) from aqueous solution.

Water contamination caused by radionuclides is a major environmental issue. Uranium (U) belongs to the actinide group of elements. Hexavalent uranium (U(VI)) is radioactively and chemically harmful and highly mobile in the environment and wastewater stream.

Study of muscle cell dedifferentiation after skeletal muscle injury of mice with a Cre-Lox system.

Background: Dedifferentiation of muscle cells in the tissue of mammals has yet to be observed. One of the challenges facing the study of skeletal muscle cell dedifferentiation is the availability of a reliable model that can confidentially distinguish differentiated cell populations of myotubes and non-fused mononuclear cells, including stem cells that can coexist within the population of cells being studied.

Methodology/principal Findings: In the current study, we created a Cre/Lox-β-galactosidase system, which can specifically tag differentiated multinuclear myotubes and myotube-generated mononuclear cells based on the activation of the marker gene, β-galactosidase.

The dose of growth factors influences the synergistic effect of vascular endothelial growth factor on bone morphogenetic protein 4-induced ectopic bone formation.

Although vascular endothelial growth factor (VEGF) has been shown to act synergistically with bone morphogenetic protein (BMP)2 and BMP4 to promote ectopic endochondral bone formation via cell-based BMP gene therapy, the optimal ratio of VEGF to either of the BMPs required to obtain this beneficial effect remains unclear. In the current study, two cell types (C2C12, NIH/3T3) were retrovirally transduced to express BMP4 only or both BMP4 and VEGF. The resulting groups of cells were tested for their cellular proliferation, in vitro mineralization capacity, survival potential, and ability to undergo ectopic bone formation when implanted into a gluteofemoral muscle pocket created in severe combined immunodeficient mice.

Bone regeneration mediated by BMP4-expressing muscle-derived stem cells is affected by delivery system.

This study investigated the delivery of bone morphogenetic protein (BMP)4-secreting muscle-derived stem cells (MDSC-B4) capable of inducing bone formation in mice using collagen gel (CG), fibrin sealant (FS), and gelatin sponge carriers. After implanting these various cell-loaded scaffolds intramuscularly or into critical-size skull defects, we measured the extent of heterotopic ossification and calvarial defect healing over a 6-week period via radiographic, radiomorphometric, histological, and micro-computed tomography analyses. As expected, in the absence of MDSC-B4, there was no ectopic ossification and only minimal calvarial regeneration using each type of scaffold.

Dominant negative Bmp5 mutation reveals key role of BMPs in skeletal response to mechanical stimulation.

Background: Over a hundred years ago, Wolff originally observed that bone growth and remodeling are exquisitely sensitive to mechanical forces acting on the skeleton. Clinical studies have noted that the size and the strength of bone increase with weight bearing and muscular activity and decrease with bed rest and disuse. Although the processes of mechanotransduction and functional response of bone to mechanical strain have been extensively studied, the molecular signaling mechanisms that mediate the response of bone cells to mechanical stimulation remain unclear.

A relationship between vascular endothelial growth factor, angiogenesis, and cardiac repair after muscle stem cell transplantation into ischemic hearts.

Objectives: We investigated whether vascular endothelial growth factor (VEGF) was associated with the angiogenic and therapeutic effects induced after transplantation of skeletal muscle-derived stem cells (MDSCs) into a myocardial infarction (MI).

Background: Because very few MDSCs were found to differentiate into new blood vessels when injected into the heart, the mechanism underlying the occurrence of angiogenesis after MDSC transplantation is currently unknown. In the present study, we used a gain- or loss-of-VEGF function approach with skeletal MDSCs engineered to express VEGF or soluble Flt1, a VEGF-specific antagonist, to identify the involvement of VEGF in MDSC transplantation-induced neoangiogenesis.

Nerve growth factor improves the muscle regeneration capacity of muscle stem cells in dystrophic muscle.

Researchers have attempted to use gene- and cell-based therapies to restore dystrophin and alleviate the muscle weakness that results from Duchenne muscular dystrophy (DMD). Our research group has isolated populations of muscle-derived stem cells (MDSCs) from the postnatal skeletal muscle of mice. In comparison with satellite cells, MDSCs display an improved transplantation capacity in dystrophic mdx muscle that we attribute to their ability to undergo long-term proliferation, self-renewal, and multipotent differentiation, including differentiation toward endothelial and neuronal lineages.

Cartilage repair using bone morphogenetic protein 4 and muscle-derived stem cells.

Objective: Muscle-derived stem cells (MDSCs) isolated from mouse skeletal muscle exhibit long-time proliferation, high self-renewal, and multipotent differentiation. This study was undertaken to investigate the ability of MDSCs that were retrovirally transduced to express bone morphogenetic protein 4 (BMP-4) to differentiate into chondrocytes in vitro and in vivo and enhance articular cartilage repair.

Methods: Using monolayer and micromass pellet culture systems, we evaluated the in vitro chondrogenic differentiation of LacZ- and BMP-4-transduced MDSCs with or without transforming growth factor beta1 (TGFbeta1) stimulation.

VEGF improves, whereas sFlt1 inhibits, BMP2-induced bone formation and bone healing through modulation of angiogenesis.

Unlabelled: We studied the interaction between VEGF and BMP2 during bone formation and bone healing. Results indicate that VEGF antagonist inhibited BMP2-elicited bone formation, whereas the delivery of exogenous VEGF enhanced BMP2-induced bone formation and bone healing through modulation of angiogenesis.

Introduction: Angiogenesis is closely associated with bone formation during normal bone development and is important for the bone formation elicited by BMP4.

Differential effect of BMP4 on NIH/3T3 and C2C12 cells: implications for endochondral bone formation.

Unlabelled: After intramuscular implantation, BMP4-expressing NIH/3T3 fibroblasts and BMP4-expressing C2C12 myoblasts can promote ectopic cartilage and bone formation. Fibroblasts tend to undergo chondrogenesis, whereas myoblasts primarily undergo osteogenesis. These results suggest that endochondral bone formation may involve different cell types, a finding that could have major implications for the tissue engineering of bone and cartilage.

Noggin improves bone healing elicited by muscle stem cells expressing inducible BMP4.

The aim of this study was to test the hypothesis that a specific antagonist may enhance the efficacy of its corresponding growth factor in a regulated tissue engineering strategy. Our prior research has led to the development of a retroviral vector that enables optimal regulated bone morphogenetic protein 4 (BMP4) expression in vitro and regulated bone formation in vivo with transduced muscle stem cells. However, when implanted in critical-sized calvarial defects, these cells led to residual bone formation without induction or bone overgrowth with induction, even at reduced cell doses.

Structural and functional healing of critical-size segmental bone defects by transduced muscle-derived cells expressing BMP4.

Background: Our previous studies have shown that muscle-derived cells, including a population of muscle stem cells, transduced with a retroviral vector expressing bone morphogenetic protein 4 (BMP4) can improve the healing of critical-size calvarial defects. However, we did not evaluate the functionality of the healed bone. The purpose of this study was to determine whether primary muscle-derived cells transduced with retroBMP4 can heal a long bone defect both structurally and functionally.

Development of a self-inactivating tet-on retroviral vector expressing bone morphogenetic protein 4 to achieve regulated bone formation.

The aims of this study were to explore the possibility of improving the design of self-inactivating (SI) retroviral vectors and to develop an SI vector that would allow optimal tet-on-regulated therapeutic gene expression. To minimize any interference between the viral promoter and the inducible promoter, we deleted different regulatory elements in the 3'LTR and examined their effects on transgene expression in transfected or transduced cells. In transfected cells, such deletions reduced the transgene expression.

Ex vivo gene therapy-induced endochondral bone formation: comparison of muscle-derived stem cells and different subpopulations of primary muscle-derived cells.

Muscle-based gene therapy and tissue engineering hold great promise for improving bone healing. However, the relative advantage of muscle-derived stem cells (MDSCs) or primary muscle-derived cells (MDCs) remains to be defined. We compared the ability of MDSCs and different subpopulations of MDCs (PP1 and PP3) to induce bone formation via ex vivo gene therapy.

Muscle-derived stem cells for musculoskeletal tissue regeneration and repair.

Muscle recently has been identified as a good source of adult stem cells that can differentiate into cells of different lineages. The most well-known muscle progenitor cells are satellite cells, which not only contribute to the replenishment of the myogenic cell pool but also can become osteoblasts, adipocytes and chondrocytes. Other populations of stem cells that appear to be distinct from satellite cells also have been discovered recently.

Converse relationship between in vitro osteogenic differentiation and in vivo bone healing elicited by different populations of muscle-derived cells genetically engineered to express BMP4.

Unlabelled: In this study, we compared the use of primary muscle-derived osteoprogenitor cells (PP6 cells) for the delivery of BMP4 to improve bone healing to that of muscle-derived non-osteoprogenitor cells (PP1 cells). Surprisingly, the use of PP1 cells resulted in an improved outcome because of the lack of adverse responses to BMP4 involving cell differentiation, proliferation, and apoptosis.

Introduction: Although researchers frequently opt to use osteogenic cells for osteogenic bone morphogenetic protein (BMP)-based ex vivo gene therapy to improve bone healing, it remains unclear whether the osteogenic potential of a cellular vehicle affects the outcome of bone healing applications.

Local ex vivo gene therapy with bone marrow stromal cells expressing human BMP4 promotes endosteal bone formation in mice.

Background: Bone loss in osteoporosis is caused by an imbalance between resorption and formation on endosteal surfaces of trabecular and cortical bone. We investigated the feasibility of increasing endosteal bone formation in mice by ex vivo gene therapy with bone marrow stromal cells (MSCs) transduced with a MLV-based retroviral vector to express human bone morphogenetic protein 4 (BMP4).

Methods: We assessed two approaches for administering transduced MSCs.

Retroviral delivery of Noggin inhibits the formation of heterotopic ossification induced by BMP-4, demineralized bone matrix, and trauma in an animal model.

Background: The heterotopic ossification of muscles, tendons, and ligaments is a common problem faced by orthopaedic surgeons. We investigated the ability of Noggin (a BMP [bone morphogenetic protein] antagonist) to inhibit heterotopic ossification.

Methods: Part 1: A retroviral vector carrying the gene encoding human Noggin was developed and used to transduce muscle-derived stem cells.

Dystrophin delivery in dystrophin-deficient DMDmdx skeletal muscle by isogenic muscle-derived stem cell transplantation.

Duchenne's muscular dystrophy (DMD) is a lethal muscle disease caused by a lack of dystrophin expression at the sarcolemma of muscle fibers. We investigated retroviral vector delivery of dystrophin in dystrophin-deficient DMD(mdx) (hereafter referred to as mdx) mice via an ex vivo approach using mdx muscle-derived stem cells (MDSCs). We generated a retrovirus carrying a functional human mini-dystrophin (RetroDys3999) and used it to stably transduce mdx MDSCs obtained by the preplate technique (MD3999).