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Open AccessArticle

Decellularized Diaphragmatic Muscle Drives a Constructive Angiogenic Response In Vivo

Stem Cells and Regenerative Medicine Lab, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova 35127 Italy
Department of Women and Children Health, University of Padova, Padova 35100, Italy
Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova 35100, Italy
Stem Cells & Regenerative Medicine Section, Developmental Biology & Cancer Programme, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
Department of Clinical Genetics, Erasmus Medical Centre, Wytemaweg 80 3015 CN, Rotterdam, The Netherlands
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(5), 1319;
Received: 19 March 2018 / Revised: 13 April 2018 / Accepted: 24 April 2018 / Published: 28 April 2018
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)
Skeletal muscle tissue engineering (TE) aims to efficiently repair large congenital and acquired defects. Biological acellular scaffolds are considered a good tool for TE, as decellularization allows structural preservation of tissue extracellular matrix (ECM) and conservation of its unique cytokine reservoir and the ability to support angiogenesis, cell viability, and proliferation. This represents a major advantage compared to synthetic scaffolds, which can acquire these features only after modification and show limited biocompatibility. In this work, we describe the ability of a skeletal muscle acellular scaffold to promote vascularization both ex vivo and in vivo. Specifically, chicken chorioallantoic membrane assay and protein array confirmed the presence of pro-angiogenic molecules in the decellularized tissue such as HGF, VEGF, and SDF-1α. The acellular muscle was implanted in BL6/J mice both subcutaneously and ortotopically. In the first condition, the ECM-derived scaffold appeared vascularized 7 days post-implantation. When the decellularized diaphragm was ortotopically applied, newly formed blood vessels containing CD31+, αSMA+, and vWF+ cells were visible inside the scaffold. Systemic injection of Evans Blue proved function and perfusion of the new vessels, underlying a tissue-regenerative activation. On the contrary, the implantation of a synthetic matrix made of polytetrafluoroethylene used as control was only surrounded by vWF+ cells, with no cell migration inside the scaffold and clear foreign body reaction (giant cells were visible). The molecular profile and the analysis of macrophages confirmed the tendency of the synthetic scaffold to enhance inflammation instead of regeneration. In conclusion, we identified the angiogenic potential of a skeletal muscle-derived acellular scaffold and the pro-regenerative environment activated in vivo, showing clear evidence that the decellularized diaphragm is a suitable candidate for skeletal muscle tissue engineering and regeneration. View Full-Text
Keywords: skeletal muscle; tissue engineering; angiogenesis; microenvironment skeletal muscle; tissue engineering; angiogenesis; microenvironment
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Alvarèz Fallas, M.E.; Piccoli, M.; Franzin, C.; Sgrò, A.; Dedja, A.; Urbani, L.; Bertin, E.; Trevisan, C.; Gamba, P.; Burns, A.J.; De Coppi, P.; Pozzobon, M. Decellularized Diaphragmatic Muscle Drives a Constructive Angiogenic Response In Vivo. Int. J. Mol. Sci. 2018, 19, 1319.

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