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PlGF–MMP-9–expressing cells restore microcirculation and efficacy of cell therapy in aged dystrophic muscle

Abstract

Sclerosis and reduced microvessel density characterize advanced stages of muscular dystrophy and hamper cell or gene delivery, precluding treatment of most individuals with Duchenne muscular dystrophy. Modified tendon fibroblasts expressing an angiogenic factor (placenta growth factor, PlGF) and a metalloproteinase (matrix metalloproteinase-9, MMP-9) are able to restore a vascular network and reduce collagen deposition, allowing efficient cell therapy in aged dystrophic mice. These data open the possibility of extending new therapies to currently untreatable individuals.

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Figure 1: In vivo migration of tendon fibroblasts.
Figure 2: Intramuscular injection of modified TFb results in increased blood vessel density.
Figure 3: Mesoangioblast intra-arterial transplantation in aged dystrophic muscle.

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Acknowledgements

We would like to thank E. Dejana (University of Milan) for the gift of HUVECs, BV13 antibody to vascular endothelial cadherin and for helpful discussion; S. Bernardini for advice on histology; and S. Iacovelli for technical help. This work was supported by grants from Duchenne Parent Project Onlus, BMW, Association Francaise contre les Myopathies, the Italian Ministry of Health and of Research (grant RBINO63EWP) and the European Community (MyoAmp).

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Contributions

C.G. prepared vectors, transduced cells and carried out most of the experimental work; S.M.C. helped with data analysis and interpretation; F.D.G. did the histology; M.C. isolated the cells and did the work on mice; G.C. coordinated the project and wrote the manuscript.

Corresponding author

Correspondence to Giulio Cossu.

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Supplementary Figs. 1–5 and Supplementary Methods (PDF 653 kb)

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Gargioli, C., Coletta, M., De Grandis, F. et al. PlGF–MMP-9–expressing cells restore microcirculation and efficacy of cell therapy in aged dystrophic muscle. Nat Med 14, 973–978 (2008). https://doi.org/10.1038/nm.1852

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