Fabrication and Prevascularization of Extracellular Matrix Derived Scaffold for Cardiac Healing
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Date
2022-05-05
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Abstract
Cardiovascular disease is a grievous and growing problem across the globe with limited therapeutic interventions available. This is due to the inability to replace fibrotic scar tissue which tends to accumulate and impair cardiac function. While stem cell-based regenerative therapies are promising, they are hindered by low survival and engraftment rates. These obstacles can be overcome by fabricating a complementary biomimetic scaffold that can support the development of an organized microvasculature and the growth of induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) to promote positive cardiac remodeling after myocardial infarction. The effectiveness of a cardiac scaffold relies on its ability to mimic the native myocardium by facilitating a multitude of cell-cell interactions and promoting the integration of implanted stem cells with the native myocardium. This has garnered attention on extracellular matrix cell sheets because they can form a completely biological, highly customizable, and tissue-specific scaffold. One of the cornerstones of designing a self-sustaining cardiac patch construct is supporting the development of a dense and highly organized microvasculature to meet the daily metabolic needs of implanted iPSC-CMs. The aim of this project was to test the potential of iPSC-ECs to form such a robust and dense microvasculature on decellularized ECM cell sheets in comparison to the previously studied HUVECs. This was achieved by co-culturing bone marrow derived human mesenchymal stem cells (hMSCs) with iPSC-ECs or HUVECs on decellularized ECM cell sheets over ten days. The results of the ECM cell sheet fabrication demonstrated that human dermal fibroblasts (HDFs) can be used to produce a highly aligned ECM which retains its structural components after decellularization. Next, the prevascularization comparison between the hMSC/iPSC-EC and the hMSC/HUVEC revealed that iPSC-ECs could form a highly aligned microvasculature like the HUVECs. In fact, the average vessel length, diameter, and intercapillary distance in the hMSC/iPSC samples was more representative of the native myocardium than the hMSC/HUVEC control. Therefore, it can be concluded that co-culturing hMSCs and iPSC-ECs encompasses great promise for replicating the cardiac microvasculature and creating a perusable network of vessels that can support stem cell growth and maturation in cardiac patch constructs. This can propel regenerative medicine a step further by providing the biomimetic ECM scaffold the self-sustaining and robust microvasculature it needs to promote lasting cardiac repair healing for the growing number of patients in cardiovascular distress.
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Tissue Engineering, Biomimetic Scaffold, 3D Scaffold, Extracellular Matrix, Cardiac Regeneration, Vascularization, Pluripotent Stem Cells, Mesenchymal Stem Cells