Abstract
Recent progress in the production and maturation of iPSC-cardiomyocytes has facilitated major advances in building bioartificial heart tissue with functional cardiomyocytes. Despite this progress, vascularizing these constructs continues to be a barrier to clinical application. One emerging strategy for vascularization uses aligned “cords” of endothelial cells in tissue grafts to guide assembly of chimeric microvessels upon graft implantation. Here, we test whether this approach can guide vascularization of a bioartificial tissue implanted on the rat heart. We find that patterned cords of human endothelial cells anastomose and become perfused with host blood by 3 days post-implantation. Immunohistochemical staining confirmed that graft-derived micro-vessels persist in the patch for 7 days. Furthermore, we noted a shift in distribution of vessels in the patch from patterned cord-associated clustering at 3 days to a more diffuse distribution pattern at 7 days. This loss of patterning corresponded to an infiltration of CD68+ cells and an increase in collagen within the patch. Upon further engraftment of patches containing both cords and human cardiomyocytes, we identified human cardiomyocytes and graft derived vasculature at the time of explant. Our findings show that patterned endothelial cords guide transient vessel patterning on the rat heart. Our results also suggest that future work should be directed at further adapting vascularization strategies to the epicardial environment and add to an important emerging dialog in cardiac cell therapy that points to the need to characterize host response prior to or in parallel with efficacy studies.
Highlights
The only definitive treatment for end stage heart failure is replacing the damaged muscle via heart transplant
Second harmonic generation microscopy16 demonstrated that compacted cords consisted of a loosely consolidated collagen core, with cells adhered around the periphery [Fig. 1(b)]
We sought to determine if bioartificial tissues containing micromolded endothelial cords could become vascularized on the heart, as we found previously when similar constructs were implanted in the abdomen of mice
Summary
The only definitive treatment for end stage heart failure is replacing the damaged muscle via heart transplant. We and others have worked to develop methods to more precisely control geometry of engineered vascular networks.12–14 One such method is micropatterning endothelial cells and stromal cells along with collagen to form aligned cord-like structures.. One such method is micropatterning endothelial cells and stromal cells along with collagen to form aligned cord-like structures.12 We showed that such endothelial cords improved vascularization and function of bioartificial liver tissues implanted in the mouse abdomen by guiding host vessel ingrowth and decreasing time to perfusion.. We showed that such endothelial cords improved vascularization and function of bioartificial liver tissues implanted in the mouse abdomen by guiding host vessel ingrowth and decreasing time to perfusion.15 Success toward vascularization by Stevens et al. and Levenberg et al. was achieved through homogenously seeding endothelial and supportive stromal cells into engineered tissues, which led to self-assembled tubular networks that became perfused upon implantation. some subsequent studies have suggested that the disorganized and tortuous nature of self-assembled networks may make them susceptible to thrombosis. we and others have worked to develop methods to more precisely control geometry of engineered vascular networks. One such method is micropatterning endothelial cells and stromal cells along with collagen to form aligned cord-like structures. We showed that such endothelial cords improved vascularization and function of bioartificial liver tissues implanted in the mouse abdomen by guiding host vessel ingrowth and decreasing time to perfusion. This method of vascular patterning
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