Dissection of heterocellular cross-talk in vascularized cardiac tissue mimetics

作者：Julian U. G. Wagner, Minh Duc Pham, Luka Nicin, Marie Hammer, Katharina Bottermann, Ting Yuan, Rahul Sharma, David John, Marion Muhly-Reinholz, Lukas Tombor, Martin Hardt, Josef Madl, Stefanie Dimmeler, Jaya Krishnan · 发表于：Journal of Molecular and Cellular Cardiology · 年份：2019 · DOI：10.1016/j.yjmcc.2019.12.005 · 被引用次数：27 · 研究领域：Tissue Engineering and Regenerative Medicine、Electrospun Nanofibers in Biomedical Applications、3D Printing in Biomedical Research

Cellular specialization and interaction with other cell types in cardiac tissue is essential for the coordinated function of cell populations in the heart. The complex interplay between cardiomyocytes, endothelial cells and fibroblasts is necessary for adaptation but can also lead to pathophysiological remodeling. To understand this complex interplay, we developed 3D vascularized cardiac tissue mimetics (CTM) to study heterocellular cross-talk in hypertrophic, hypoxic and fibrogenic environments. This 3D platform responds to physiologic and pathologic stressors and mimics the microenvironment of diseased tissue. In combination with endothelial cell fluorescence reporters, these cardiac tissue mimetics can be used to precisely visualize and quantify cellular and functional responses upon stress stimulation. Utilizing this platform, we demonstrate that stimulation of α/β-adrenergic receptors with phenylephrine (PE) promotes cardiomyocyte hypertrophy, metabolic maturation and vascularization of CTMs. Increased vascularization was promoted by conditioned medium of PE-stimulated cardiomyocytes and blocked by inhibiting VEGF or upon β-adrenergic receptor antagonist treatment, demonstrating cardiomyocyte-endothelial cross-talk. Pathophysiological stressors such as severe hypoxia reduced angiogenic sprouting and increased cell death, while TGF β2 stimulation increased collagen deposition concomitant to endothelial-to-mesenchymal transition. In sum, we have developed a cardiac 3D cult...