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1.
Nat Biotechnol ; 29(10): 934-41, 2011 Sep 25.
Article in English | MEDLINE | ID: mdl-21947029

ABSTRACT

Experimental animals with myelin disorders can be treated by transplanting oligodendrocyte progenitor cells (OPCs) into the affected brain or spinal cord. OPCs have been isolated by their expression of gangliosides recognized by mAb A2B5, but this marker also identifies lineage-restricted astrocytes and immature neurons. To establish a more efficient means of isolating myelinogenic OPCs, we sorted fetal human forebrain cells for CD140a, an epitope of platelet derived growth factor receptor (PDGFR)α, which is differentially expressed by OPCs. CD140a(+) cells were isolated as mitotic bipotential progenitors that initially expressed neither mature neuronal nor astrocytic phenotypic markers, yet could be instructed to either oligodendrocyte or astrocyte fate in vitro. Transplanted CD140a(+) cells were highly migratory and robustly myelinated the hypomyelinated shiverer mouse brain more rapidly and efficiently than did A2B5(+)cells. Microarray analysis of CD140a(+) cells revealed overexpression of the oligodendroglial marker CD9, suggesting that CD9(+)/CD140a(+) cells may constitute an even more highly enriched population of myelinogenic progenitor cells.


Subject(s)
Cell Movement , Myelin Sheath/metabolism , Oligodendroglia/cytology , Oligodendroglia/transplantation , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Stem Cell Transplantation , Stem Cells/cytology , Animals , Astrocytes/cytology , Astrocytes/metabolism , Axons/metabolism , Cell Proliferation , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Fetal Stem Cells/cytology , Fetal Stem Cells/metabolism , Fetus/cytology , Gene Expression Regulation , Humans , Mice , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction/genetics , Stem Cells/metabolism , Tetraspanin 29/metabolism
2.
Am J Physiol Heart Circ Physiol ; 300(5): H1841-52, 2011 May.
Article in English | MEDLINE | ID: mdl-21335464

ABSTRACT

Mammalian enabled (Mena) of the Drosophila enabled/vasodilator-stimulated phosphoprotein gene family is a cytoskeletal protein implicated in actin regulation and cell motility. Cardiac Mena expression is enriched in intercalated discs (ICD), the critical intercellular communication nexus between adjacent muscle cells. We previously identified Mena gene expression to be a key predictor of human and murine heart failure (HF). To determine the in vivo function of Mena in the heart, we assessed Mena protein expression in multiple HF models and characterized the effects of genetic Mena deletion on cardiac structure and function. Immunoblot analysis revealed significant upregulation of Mena protein expression in left ventricle tissue from patients with end-stage HF, calsequestrin-overexpressing mice, and isoproterenol-infused mice. Characterization of the baseline cardiac function of adult Mena knockout mice (Mena(-/-)) via echocardiography demonstrated persistent cardiac dysfunction, including a significant reduction in percent fractional shortening compared with wild-type littermates. Electrocardiogram PR and QRS intervals were significantly prolonged in Mena(-/-) mice, manifested by slowed conduction on optical mapping studies. Ultrastructural analysis of Mena(-/-) hearts revealed disrupted organization and widening of ICD structures, mislocalization of the gap junction protein connexin 43 (Cx43) to the lateral borders of cardiomyoycytes, and increased Cx43 expression. Furthermore, the expression of vinculin (an adherens junction protein) was significantly reduced in Mena(-/-) mice. We report for the first time that genetic ablation of Mena results in cardiac dysfunction, highlighted by diminished contractile performance, disrupted ICD structure, and slowed electrical conduction.


Subject(s)
Cytoskeletal Proteins/physiology , Heart Failure/physiopathology , Heart/physiopathology , Microfilament Proteins/physiology , Animals , Connexin 43/metabolism , Cytoskeletal Proteins/deficiency , Cytoskeletal Proteins/genetics , Disease Models, Animal , Gap Junctions/metabolism , Gap Junctions/ultrastructure , Heart Failure/metabolism , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocardial Contraction/physiology , Myocardium/metabolism , Myocardium/ultrastructure , Phosphorylation
3.
Physiol Genomics ; 32(2): 182-9, 2008 Jan 17.
Article in English | MEDLINE | ID: mdl-17971502

ABSTRACT

Numerous genetically engineered animal models of heart failure (HF) exhibit multiple characteristics of human HF, including aberrant beta-adrenergic signaling. Several of these HF models can be rescued by cardiac-targeted expression of the Gbetagamma inhibitory carboxy-terminus of the beta-adrenergic receptor kinase (betaARKct). We recently reported microarray analysis of gene expression in multiple animal models of HF and their betaARKct rescue, where we identified gene expression patterns distinct and predictive of HF and rescue. We have further investigated the muscle LIM protein knockout model of HF (MLP-/-), which closely parallels human dilated cardiomyopathy disease progression and aberrant beta-adrenergic signaling, and their betaARKct rescue. A group of known and novel genes was identified and validated by quantitative real-time PCR whose expression levels predicted phenotype in both the larger HF group and in the MLP-/- subset. One of these novel genes is herein identified as Nogo, a protein widely studied in the nervous system, where it plays a role in regeneration. Nogo expression is altered in HF and normalized with rescue, in an isoform-specific manner, using left ventricular tissue harvested from both animal and human subjects. To investigate cell type-specific expression of Nogo in the heart, immunofluorescence and confocal microscopy were utilized. Nogo expression appears to be most clearly associated with cardiac fibroblasts. To our knowledge, this is the first report to demonstrate the relationship between Nogo expression and HF, including cell-type specificity, in both mouse and human HF and phenotypic rescue.


Subject(s)
Heart Failure/pathology , Muscle Proteins/genetics , Myelin Proteins/genetics , Myocardium/pathology , Animals , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/metabolism , Cardiomyopathy, Dilated/pathology , Gene Deletion , Gene Expression Profiling , Heart Failure/genetics , Heart Failure/metabolism , Humans , Immunohistochemistry , LIM Domain Proteins , Male , Mice , Mice, Knockout , Muscle Proteins/metabolism , Myelin Proteins/metabolism , Myocardium/metabolism , Nogo Proteins , Oligonucleotide Array Sequence Analysis , beta-Adrenergic Receptor Kinases/genetics , beta-Adrenergic Receptor Kinases/metabolism
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