Transgenic Expression of Laminin α1 Chain Does Not Prevent Muscle Disease in the mdx Mouse Model for Duchenne Muscular Dystrophy

Gawlik, Kinga I.; Oliveira, Bruno Menezes de; Durbeej, Madeleine

doi:10.1016/j.ajpath.2010.12.030

Cited by 18 publications

(17 citation statements)

References 35 publications

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“…For instance, pre-clinical animal studies have been performed injecting laminin 111 into dystrophic mice despite the lack of α1 in the muscle [36]. However, these results are controversial since follow-up transgenic laminin 111 studies show no benefit in the mdx model [37]. Our results show for the first time that there are significant functional differences between the laminin α1 and α2 chains.…”

Section: Discussionmentioning

confidence: 77%

Laminin 521 maintains differentiation potential of mouse and human satellite cell-derived myoblasts during long-term culture expansion

Penton

Badarinarayana

Prisco³

et al. 2016

Skeletal Muscle

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BackgroundLarge-scale expansion of myogenic progenitors is necessary to support the development of high-throughput cellular assays in vitro and to advance genetic engineering approaches necessary to develop cellular therapies for rare muscle diseases. However, optimization has not been performed in order to maintain the differentiation capacity of myogenic cells undergoing long-term cell culture. Multiple extracellular matrices have been utilized for myogenic cell studies, but it remains unclear how different matrices influence long-term myogenic activity in culture. To address this challenge, we have evaluated multiple extracellular matrices in myogenic studies over long-term expansion.MethodsWe evaluated the consequence of propagating mouse and human myogenic stem cell progenitors on various extracellular matrices to determine if they could enhance long-term myogenic potential. For the first time reported, we comprehensively examine the effect of physiologically relevant laminins, laminin 211 and laminin 521, compared to traditionally utilized ECMs (e.g., laminin 111, gelatin, and Matrigel) to assess their capacity to preserve myogenic differentiation potential.ResultsLaminin 521 supported increased proliferation in early phases of expansion and was the only substrate facilitating high-level fusion following eight passages in mouse myoblast cell cultures. In human myoblast cell cultures, laminin 521 supported increased proliferation during expansion and superior differentiation with myotube hypertrophy. Counterintuitively however, laminin 211, the native laminin isoform in resting skeletal muscle, resulted in low proliferation and poor differentiation in mouse and human cultures. Matrigel performed excellent in short-term mouse studies but showed high amounts of variability following long-term expansion.ConclusionsThese results demonstrate laminin 521 is a superior substrate for both short-term and long-term myogenic cell culture applications compared to other commonly utilized substrates. Since Matrigel cannot be used for clinical applications, we propose that laminin 521 could possibly be employed in the future to provide myoblasts for cellular therapy directed clinical studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-016-0116-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 77%

Laminin 521 maintains differentiation potential of mouse and human satellite cell-derived myoblasts during long-term culture expansion

Penton

Badarinarayana

Prisco³

et al. 2016

Skeletal Muscle

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“…Injection of laminin-111 protein in the mdx mouse increased expression of α7-integrin, improved skeletal muscle stem cells function and regenerative capacity, stabilized the sarcolemma, and protected muscle from exercise-induced damage (190,191). However, a different study with transgenic expression of the laminin α1 chain to enhance heterotrimer formation of laminin-111 in the mdx mouse reported no improvement of the dystrophic symptoms (83), indicating that further studies are required to verify the functionality of laminin-111 protein therapy in DMD.…”

Section: α7-integrin Upregulation/laminin-111mentioning

confidence: 88%

The Pathogenesis and Therapy of Muscular Dystrophies

Guiraud

Aartsma‐Rus

Vieira

et al. 2015

Annu. Rev. Genom. Hum. Genet.

261

286

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Current molecular genomic approaches to human genetic disorders have led to an explosion in the identification of the genes and their encoded proteins responsible for these disorders. The identification of the gene altered by mutations in Duchenne and Becker muscular dystrophy was one of the earliest examples of this paradigm. The nearly 30 years of research partly outlined here exemplifies the road that similar current gene discovery protocols will be expected to travel, albeit much more rapidly owing to improved diagnosis of genetic disorders and an understanding of the spectrum of mutations thought to cause them. The identification of the protein dystrophin has led to a new understanding of the muscle cell membrane and the proteins involved in membrane stability, as well as new candidate genes for additional forms of muscular dystrophy. Animal models identified with naturally occurring mutations and developed by genetic manipulation have furthered the understanding of disease progression and underlying pathology. The biochemistry and molecular analysis of patient samples have led to the different dystrophin-dependent and -independent therapies that are currently close to or in human clinical trials. The lessons learned from decades of research on dystrophin have benefited the field of human genetics.

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“…Intravenous infusion of human LM-511 is also a potential therapy, as it will not be rejected by the host immune system but should improve glomerular permselectivity with successful incorporation into the GBM. Interestingly, intramuscular injection of laminin-111 protein into mdx mice, a model of Duchenne muscular dystrophy, was shown to ameliorate muscular dystrophy by increasing integrin α7 (44), although, paradoxically, transgenic expression of Lamα1 in mdx muscle fails to improve dystrophic features (45).…”

Section: Discussionmentioning

confidence: 99%

Forced expression of laminin β1 in podocytes prevents nephrotic syndrome in mice lacking laminin β2, a model for Pierson syndrome

Suh

Jarad

VanDeVoorde

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Pierson syndrome is a congenital nephrotic syndrome with ocular and neurological defects caused by mutations in LAMB2 , the gene encoding the basement membrane protein laminin β2 (Lamβ2). It is the kidney glomerular basement membrane (GBM) that is defective in Pierson syndrome, as Lamβ2 is a component of laminin-521 (LM-521; α5β2γ1), the major laminin in the mature GBM. In both Pierson syndrome and the Lamb2 −/− mouse model for this disease, laminin β1 (Lamβ1), a structurally similar homolog of Lamβ2, is marginally increased in the GBM, but it fails to fully compensate for the loss of Lamβ2, leading to the filtration barrier defects and nephrotic syndrome. Here we generated several lines of Lamβ1 transgenic mice and used them to show that podocyte-specific Lamβ1 expression in Lamb2 −/− mice abrogates the development of nephrotic syndrome, correlating with a greatly extended lifespan. In addition, the more Lamβ1 was expressed, the less urinary albumin was excreted. Transgenic Lamβ1 expression increased the level of Lamα5 in the GBM of rescued mice, consistent with the desired increased deposition of laminin-511 (α5β1γ1) trimers. Ultrastructural analysis revealed occasional knob-like subepithelial GBM thickening but intact podocyte foot processes in aged rescued mice. These results suggest the possibility that up-regulation of LAMB1 in podocytes, should it become achievable, would likely lessen the severity of nephrotic syndrome in patients carrying LAMB2 mutations.

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Transgenic Expression of Laminin α1 Chain Does Not Prevent Muscle Disease in the mdx Mouse Model for Duchenne Muscular Dystrophy

Cited by 18 publications

References 35 publications

Laminin 521 maintains differentiation potential of mouse and human satellite cell-derived myoblasts during long-term culture expansion

Laminin 521 maintains differentiation potential of mouse and human satellite cell-derived myoblasts during long-term culture expansion

The Pathogenesis and Therapy of Muscular Dystrophies

Forced expression of laminin β1 in podocytes prevents nephrotic syndrome in mice lacking laminin β2, a model for Pierson syndrome

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