Prevascular structures promote vascularization in engineered human adipose tissue constructs upon implantation

Abstract Vascularization is still one of the most important limitations for the survival of engineered tissues after implantation. In this study, we aim to improve the in vivo vascularization of engineered adipose tissue by pre-forming vascular structures within in vitro-engineered adipose tissue constructs that can integrate with the host vascular system upon implantation. Different cell culture media were tested and different amounts of human adipose tissue-derived mesenchymal stromal cells (ASC) and human umbilical vein endothelial cells (HUVEC) were combined in spheroid co-cultures to obtain optimal conditions for the generation of prevascularized adipose tissue constructs. Immunohistochemistry revealed that prevascular structures were formed in the constructs only when 20% ASC and 80% HUVEC were combined and cultured in a 1:1 mixture of endothelial cell medium and adipogenic medium. Moreover, the ASC in these constructs accumulated lipid and expressed the adipocyte-specific gene fatty acid binding protein-4. Implantation of prevascularized ASC/HUVEC constructs in nude mice resulted in a significantly higher amount of vessels (3717 vessels/mm2) within the constructs compared to non-prevascularized constructs composed only of ASC (3 4 vessels/mm2). Moreover, a subset of the pre-formed human vascular structures (3.6±4.2 structures/mm2) anastomosed with the mouse vasculature as indicated by the presence of intravascular red blood cells. Our results indicate that pre-formed vascular structures within in vitro-engineered adipose tissue constructs can integrate with the host vascular system and improve the vascularization upon implantation.

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