FABRICATION OF PREVASCULARIZED CELL-DERIVED EXTRACELLULAR MATRIX BASED BIOMIMETIC TISSUE CONSTRUCTS FOR MULTIPLE TISSUE ENGINEERING

Tissue engineering and regenerative medicine has been vast developing since the past decade. A preformed functional vascular network provides effective solution for solving the mass transportation problem. With the support of mural cells, endothelial cells (ECs) can form microvessels within engineered tissues. As one of the important mural cells, human mesenchymal stem cells (hMSCs) not only stabilize the engineered microvessel network, but also preserve their multi-potency when grown under optimal culture conditions. A prevascularized hMSC/ECM sheet fabricated by the combination of hMSCs, ECs and a naturally derived nanofibrous extracellular matrix (ECM) scaffold offers great opportunity for engineering mechanically strong and completely biological 3D prevascularized tissues. Moreover, for regeneration of highly organized tissues such as skeletal, cardiac, and neural tissues, it is critical to create aligned vasculatures within the constructs, which not only provide inlets/outlets for ease of vessel anastomosis, but also play important roles in tissue functional performance. The topographical stimulation enhanced the structure, density, and length of the vascular networks by promoting pro-angiogenic growth factor secretion and guiding neovasculature orientation. The matrix remodeling enzymatic activity assessment revealed that CD166 mediated MMP-2 activation played a major role in angiogenesis and vasculature remodeling direction. Preliminary studies have shown that hMSCs can be transplanted to improve nerve regeneration. Hypoxia pretreated hMSCs had an improved potential for peripheral nerve regeneration. The future works can focus on studying the neural protective functions of MSCs, and how prevascularized scaffolds can restore the oxygen supply towards the hypoxic region upon ischemia or injury. In summary, prevascularized nanofibrous ECM constructs can serve as building blocks to engineer 3D oriented tissues with aligned vasculatures, while preserving the therapeutic potential of bulk hMSCs. Together, this study paved the way for engineering large organs, and provided a perspective on replicate native cell/ECM/vessel structure to benefit regenerative medicine