Abstract
In this study, we investigate the translational potential of a novel combined construct using an FDA-approved decellularized porcine small intestinal submucosa extracellular matrix (SIS-ECM) seeded with human or porcine mesenchymal stem cells (MSCs) for cardiovascular indications. With the emerging success of individual component in various clinical applications, the combination of SIS-ECM with MSCs could provide additional therapeutic potential compared to individual components alone for cardiovascular repair. We tested the in vitro effects of MSC-seeding on SIS-ECM on resultant construct structure/function properties and MSC phenotypes. Additionally, we evaluated the ability of porcine MSCs to modulate recipient graft-specific response towards SIS-ECM in a porcine cardiac patch in vivo model. Specifically, we determined: 1) in vitro loading-capacity of human MSCs on SIS-ECM, 2) effect of cell seeding on SIS-ECM structure, compositions and mechanical properties, 3) effect of SIS-ECM seeding on human MSC phenotypes and differentiation potential, and 4) optimal orientation and dose of porcine MSCs seeded SIS-ECM for an in vivo cardiac application. In this study, histological structure, biochemical compositions and mechanical properties of the FDA-approved SIS-ECM biomaterial were retained following MSCs repopulation in vitro. Similarly, the cellular phenotypes and differentiation potential of MSCs were preserved following seeding on SIS-ECM. In a porcine in vivo patch study, the presence of porcine MSCs on SIS-ECM significantly reduced adaptive T cell response regardless of cell dose and orientation compared to SIS-ECM alone. These findings substantiate the clinical translational potential of combined SIS-ECM seeded with MSCs as a promising therapeutic candidate for cardiac applications.
Highlights
Fetal bovine serum (FBS) premium select was purchased from Atlanta Biologicals (Lawrenceville, GA). 96-well tissue culture plates were from Corning Inc. (Corning, NY)
To confirm that human MSCs (hMSCs) can be seeded onto the SIS-ECM biomaterial, the cells were transduced with eGFP using a lentiviral vector and cultured on normal tissue plastic or SIS-ECM
Background fluorescence from control SIS-ECM was minimal (Fig 1C), and seeded eGFP-labeled hMSCs were observed to adhere on the three-dimensional SIS-ECM (Fig 1D)
Summary
Several animal and clinical studies have demonstrated the ability of decellularized porcine SIS-ECM to mediate tissue repair in a range of regenerative applications, including wound healing [1,2,3,4], bladder regeneration [5,6,7], tendon graft [8] gastrointestinal grafts [9,10,11] and PLOS ONE | DOI:10.1371/journal.pone.0153412 April 12, 2016Mesenchymal Stem Cell and Porcine Small Intestinal Submucosa cardiovascular repairs [12,13,14,15,16,17,18]. SIS-ECM patches have been utilized for surgical correction of congenital cardiovascular defects, including pericardial, aortic and pulmonary artery reconstruction, vascular and septal defect restoration, as well as valvular repair [12,13,14,15,16,17,18]. These studies demonstrate SIS-ECM compatibility with host cardiovascular tissues to provide structural support and potential for enhancement of regenerative responses to repair cardiovascular defects. The mechanism by which MSCs modulate vascular and cardiac tissue repair have been associated with release of a diverse range of pro-angiogenic, pro-migratory, pro-survival and immunomodulatory cytokines, capable of modulating local effector cell function [28, 29]
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