Challenges: Cell transplantation and gene therapy in muscular dystrophy

Morgan, Jennifer E.; Partridge, Terence A.

doi:10.1002/bies.950140913

Cited by 36 publications

(15 citation statements)

References 46 publications

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“…Thus, it will be useful to provide a scientific basis upon which alternative treatments could be developed. In addition, the actions of CTLs on muscle are believed to interfere with successful myoblast transfer or adenoviral gene delivery (50,51), both of which are potential therapies for muscular dystrophy. Therefore, a better understanding of the interactions of CTLs and muscle cells is fundamental for the success of gene therapy.…”

Section: Discussionmentioning

confidence: 99%

Myonuclear apoptosis in dystrophic mdx muscle occurs by perforin-mediated cytotoxicity.

Spencer

Walsh²,

Dorshkind³

et al. 1997

J. Clin. Invest.

157

124

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Myonuclear apoptosis is an early event in the pathology of dystrophin-deficient muscular dystrophy in the mdx mouse. However, events that initiate apoptosis in muscular dystrophy are unknown, and whether elimination of apoptosis can ameliorate subsequent muscle wasting remains a major question. We have tested the hypothesis that cytotoxic T-lymphocytes initiate myonuclear apoptosis in dystrophic muscle, and examined whether perforin-mediated cytotoxicity plays a role in the pathophysiology of muscular dystrophy. Mdx mice showed muscle invasion by cytotoxic T cells and helper T cells at the onset of histologically detectable muscle fiber pathology. At this time, perforin-expressing cells were also present at elevated concentration. Mdx mice depleted of CD8 ϩ cells showed a significant reduction of apoptotic myonuclei concentration and a reduction in necrosis, judged by macrophage invasion of muscle fibers. Double-mutant mice, deficient in dystrophin and perforin, showed nearly complete absence of myonuclear apoptosis, and a significant reduction in the concentration of macrophages in the connective tissue surrounding muscle fibers. However, muscle fiber invasion by macrophages was not reduced significantly in double mutant mice. Thus, cytotoxic T-lymphocytes contribute significantly to apoptosis and necrosis in mdx dystrophy, and perforin-mediated killing is primarily responsible for myonuclear apoptosis. ( J. Clin. Invest. 1997. 99:2745-2751.)

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Section: Discussionmentioning

confidence: 99%

Myonuclear apoptosis in dystrophic mdx muscle occurs by perforin-mediated cytotoxicity.

Spencer

Walsh²,

Dorshkind³

et al. 1997

J. Clin. Invest.

157

124

View full text Add to dashboard Cite

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“…The secretion of MMPs by skeletal myoblasts and satellite cells is clearly consistent with their observed ability to migrate through the basal lamina. The secretion of matrix-degrading metalloproteases could also be a n important factor in recent experiments in which skeletal muscle myoblasts transplanted into skeletal muscle (Hughes and Blau, 1990;Karpati et al, 1989Karpati et al, , 1993Naffakh et al, 1993;Tremblay et al, 1993;Morgan and Partridge, 1992;Partridge et al, 1989;Morgan et al, 1993) appear capable of passing through a n established basal lamina and fusing into existing myofibers. However, the present study indicates an absence of detectable stromelysin expression by satellite cells, which may limit their capacity to degrade basal lamina components, particularly those which are non-collagenous.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and secretion of matrix‐degrading metalloproteases by human skeletal muscle satellite cells

Guérin

Holland

1995

Developmental Dynamics

122

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The expression of matrix-degrading metalloproteases (MMPs) by human skeletal muscle satellite cells was investigated by zymography of cell culture media and by Northern blot analysis of mRNA prepared from satellite cells. Zymography in gelatin substrate gels revealed that satellite cells constitutively synthesize and secrete 72 kDa gelatinase (MMP-2). In addition, treatment of satellite cell cultures with phorbol ester resulted in an induction of 92 kDa gelatinase (MMP-9) activity. On casein substrate gels, little or no proteolytic activity was detectable in control or phorbol ester treated satellite cell cultures, suggesting that compared to fibroblasts, satellite cells secrete little or no interstitial collagenase (MMP-1) or stromelysin (MMP-3) activity. Northern blotting, however, revealed that there is detectable expression of mRNA transcripts encoding MMP-1 in satellite cell cultures, and that increased accumulation of MMP-1 mRNA transcripts occurs upon treatment of these cells with phorbol ester. In contrast, no constitutive, or induced expression of transcripts encoding MMP-3 was detectable in satellite cells. These findings show that satellite cells can synthesize and secrete selected members of the MMP family and suggest that skeletal muscle cells may participate directly in remodelling of the extracellular matrix during myogenesis and the regeneration of skeletal muscle. 0 1995 Wiley-Liss, Inc.

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“…Primary myoblasts isolated from the muscle of neonatal mice and transplanted into mdx mice were the first successful stem cell transplants in the field. 89,90 Although these results were promising, the search for more pluripotent, ancestral progenitors led to the isolation of additional stem cell populations from distinct tissue compartments, such as bone marrow and stroma, muscle, skin, and heart. Isolated from fetal, neonatal, or adult mice and using Hoechst dye exclusion or preplating techniques, stem cells have been frequently transplanted into the mdx mouse, because the ability to restore dystrophin protein expression provides a useful marker of successful transplantation.…”

Section: Therapeutic Restoration Of Dgc: Stem Cell Transplantationmentioning

confidence: 99%

The Dystrophin Glycoprotein Complex

Lapidos

Kakkar

McNally

2004

Circulation Research

437

204

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Abstract-The dystrophin glycoprotein complex (DGC) is a specialization of cardiac and skeletal muscle membrane. This large multicomponent complex has both mechanical stabilizing and signaling roles in mediating interactions between the cytoskeleton, membrane, and extracellular matrix. Dystrophin, the protein product of the Duchenne and X-linked dilated cardiomyopathy locus, links cytoskeletal and membrane elements. Mutations in additional DGC genes, the sarcoglycans, also lead to cardiomyopathy and muscular dystrophy. Animal models of DGC mutants have shown that destabilization of the DGC leads to membrane fragility and loss of membrane integrity, resulting in degeneration of skeletal muscle and cardiomyocytes. Vascular reactivity is altered in response to primary degeneration in striated myocytes and arises from a vascular smooth muscle cell-extrinsic mechanism. Key Words: dystrophin Ⅲ sarcoglycan Ⅲ membrane Ⅲ cardiomyocyte Ⅲ skeletal muscle S triated muscle contraction requires precise and coordinated activity of both the nervous and somatic systems, from excitation of individual myofibers at the neuromuscular junction to the ATP-regulated power stroke of myosin. Muscle contraction in both heart and skeletal muscle results in cellular deformation and shortening. Throughout this process, the contractile machinery inside the myofibers must remain intimately connected with the membrane and extracellular matrix. Without this association, movement would be improperly transmitted and myocytes would risk damage to their membranes. One function of the dystrophin glycoprotein complex (DGC) is to provide a strong mechanical link from the intracellular cytoskeleton to the extracellular matrix. The DGC is composed of transmembrane, cytoplasmic, and extracellular proteins. With the emergence of data on the numerous and diverse components of the complex and how they interact with one another, it has become increasingly clear that the DGC holds both structural and signal transduction properties. Known components of the DGC include dystrophin, sarcoglycans, dystroglycan, dystrobrevins, syntrophins, sarcospan, caveolin-3, and NO synthase (Figure 1). These proteins are found in differing combinations depending on muscle type (Table).

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Challenges: Cell transplantation and gene therapy in muscular dystrophy

Cited by 36 publications

References 46 publications

Myonuclear apoptosis in dystrophic mdx muscle occurs by perforin-mediated cytotoxicity.

Myonuclear apoptosis in dystrophic mdx muscle occurs by perforin-mediated cytotoxicity.

Synthesis and secretion of matrix‐degrading metalloproteases by human skeletal muscle satellite cells

The Dystrophin Glycoprotein Complex

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