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Early Vascular Cells Improve Microvascularization within 3D Cardiac Spheroids.

INTRODUCTION
A key obstacle in the creation of engineered cardiac tissues of clinically relevant sizes is limited diffusion of oxygen and nutrients. Thus, there is a need for organized vascularization within a 3D tissue environment. Human induced pluripotent stem cell (hiPSC) derived early vascular cells (EVCs) have shown to improve organization of vascular networks within hydrogels. We hypothesize that introduction of EVCs into 3D microtissue spheroids will lead to increased microvascular formation and improve spheroid formation.


METHODS
HiPSC derived-cardiomyocytes (CM) were co-cultured with human adult ventricular cardiac fibroblasts (FB), and either human umbilical vein endothelial cells (HUVEC) or hiPSC-derived EVCs for 72 hours to form mixed cell spheroids. Three different groups of cell ratios were tested: Group 1 (control) consisted of CM:FB:HUVEC 70:15:15, Group 2 consisted of CM:FB:EVC 70:15:15 and Group 3 consisted of CM:FB:EVC 40:15:45. Vascularization, cell distribution, and cardiac function were investigated.


RESULTS
Improved microvasculature was found in EVC spheroids with new morphologies of endothelial organization not found in Group 1 spheroids. CMs were found in a core-shell type distribution in Group 1 spheroids, but more uniformly distributed in EVC spheroids. Contraction rate increased into Group 2 spheroids compared to Group 1 spheroids.


CONCLUSION
The triculture of CM, FB and EVC within a multicellular cardiac spheroid promotes microvascular formation and cardiac spheroid contraction.