Abstract
The administration of trophic factors (TFs) released by mesenchymal stromal cells (MSCs) as therapy for cardiovascular diseases requires a delivery vehicle capable of binding and releasing the TF in a sustained manner. We hypothesized that hydrogels derived from cardiac decellularized extracellular matrix (cardiac dECM) bind MSC secretome-derived TF and release these in a sustained fashion. Pig-derived ventricular tissue was decellularized, milled to powder, digested, and assembled as a hydrogel upon warming at 37 °C. The conditioned medium (CMed) of adipose tissue-derived stromal cells (ASC) was collected, concentrated, and incorporated into the hydrogel at 1×, 10×, and 100× the original concentration. The release of 11 ASC-secreted factors (angiopoietin-1, angiopoietin-2, fibroblast growth factor-1, hepatocyte growth factor, platelet-derived growth factor-AA, vascular endothelial growth factor, interleukin-1β, interleukin-6, interleukin-8, CCL2, and matrix metalloproteinase-1) from hydrogels was immune assessed. Bioactivity was determined by endothelial cell proliferation, function, and assessment of endothelial mesenchymal transition. We showed that dECM hydrogels could be loaded with human ASC-secreted TFs, which are released in a sustained manner for several days subsequently. Different trophic factors had different release kinetics, which correlates with the initial concentration of CMed in the hydrogel. We observed that the more concentrated was the hydrogel, the more inflammation-related cytokines, and the less pro-regenerative TFs were released. Finally, we showed that the factors secreted by the hydrogel are biologically active as these influence cell behavior. The use of dECM hydrogels as a platform to bind and release paracrine factors secreted by (mesenchymal) cells is a potential alternative in the context of cardiovascular regeneration.
Highlights
The use of stem cells to treat heart failure has been under investigation for two decades
Genomic DNA quantification showed around 99% of reduction in DNA content, with decellularized extracellular matrix (dECM) presenting less than 50 ng mg−1 of DNA per dry weight, the standard value for successful decellularization [21]
Trophic factor relative concentration varies according to the level of concentration of the conditioned medium (CMed) The relative concentration, i.e. the proportion of each released trophic factors (TFs), for all the three release waves, in the analyzed medium varied according to the level of concentration of the CMed
Summary
The use of stem cells to treat heart failure has been under investigation for two decades. Besides constructive stem cells that differentiate directly to cardiomyocytes or endothelial cells, reconstruction of the damaged myocardium may prevent and reverse disease progression Heart failure is both the result of a deteriorated pump function along with an exaggerated response of the connective tissue in the form of excessive extracellular matrix deposition [1,2,3]. Tissue homeostasis is maintained by the tissue stroma, i.e. extracellular matrix, mesenchymal cells and vasculature As it appears, cultured stromal cells from bone marrow (BM-MSC) or adipose tissue (ASC) are potent tissue remodelers via secretion of a plethora of paracrine factors that suppress apoptosis, promote the proliferation of parenchyma, modulate immune reactions and are pro-angiogenic [4,5,6]. Two significant mechanisms that underlie cardiac fibrosis and heart failure and which are influenced by TF are endothelial mesenchymal transition (EndMT) and myofibroblast differentiation of cardiac fibroblasts [9, 10]
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