Prevascularization of natural nanofibrous extracellular matrix for engineering completely biological three‐dimensional prevascularized tissues for diverse applications

Abstract

Self-sustainability after implantation is one of the critical obstacles facing large engineered tissues. A preformed functional vascular network provides an effective solution for solving the mass transportation problem. With the support of mural cells, endothelial cells (ECs) can form microvessels within engineered tissues. As an important mural cell, 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/extracellular matrix (ECM) sheet fabricated by the combination of hMSCs, ECs and a naturally derived nanofibrous ECM scaffold offers great opportunity for engineering mechanically strong and completely biological three-dimensional prevascularized tissues. The objective of this study was to create a prevascularized hMSC/ECM sheet by co-culturing ECs and hMSCs on a nanofibrous ECM scaffold. Physiologically low oxygen (2% O ) was introduced during the 7 day hMSC culture to preserve the stemness of hMSCs and thereby their capability to secrete angiogenic factors. The ECs were then included to form microvessels under normal oxygen (20% O ) for up to 7 days. The results showed that a branched and mature vascular network was formed in the co-culture condition. Angiogenic factors vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiopoietin-1 (Ang-1) were significantly increased by low-oxygen culture of hMSCs, which further stabilized and supported the maturation of microvessels. A differentiation assay of the prevascularized ECM scaffold demonstrated a retained hMSC multi-potency in the hypoxia cultured samples. The prevascularized hMSC/ECM sheet holds great promise for engineering three-dimensional prevascularized tissues for diverse applications.

Decellularized Extracellular Matrix Materials for Cardiac Repair and Regeneration

“…In addition to tissue derived dECM, there have been studies on cardiac‐specific dECM derived from cardiac fibroblasts grown in sheets, called fibroblast‐derived matrix (FDM) . These scaffolds can be used as patches, either directly or with additional cell seeing.…”

“…The study proposes a similar mechanism for repair presented in the earlier studies by Mewhort et al, where GF factor release from the SIS patch induces activation of the epicardium, although quantification of this effect was not fully assessed. Chang et al developed an SIS patch seeded with MSCs for cardiac repair . While tested only on healthy pigs, patch implantation reduced T‐cell response at both high and low MSC doses when compared to implantation of SIS alone, although B cell response was similar across all groups.…”

Mesenchymal stem cells for pre-vascularization of engineered tissues

“…25 In order to mimic the native microenvironment more closely, we have developed decellularized ECM from human dermal fibroblast sheets. 26 Importantly, these ECM sheets inherit the nano-fibrous structure of ECM and support robust vascular network formation during MSC-EC co-culture. 26 As an alternative for natural ECM components, various biodegradable and biocompatible synthetic polymers can be used to develop scaffolds for co-cultures, such as polycaprolactone (PCL), poly(l-lactic acid) (PLA), poly(glycolic acid) (PGA), and poly(lacticco-glycolic) acid (PLGA).…”

“…26 Importantly, these ECM sheets inherit the nano-fibrous structure of ECM and support robust vascular network formation during MSC-EC co-culture. 26 As an alternative for natural ECM components, various biodegradable and biocompatible synthetic polymers can be used to develop scaffolds for co-cultures, such as polycaprolactone (PCL), poly(l-lactic acid) (PLA), poly(glycolic acid) (PGA), and poly(lacticco-glycolic) acid (PLGA). 27 Although these synthetic materials are able to mimic the physical properties of ECM to some extent, they need to be further functionalized to create a more favorable environment for the cells.…”

“…7,8 Consequently, in order to develop a capillary network in tissue scaffolds various research groups over past several years have investigated the outcome of MSC-EC co-cultures. [9][10][11][12] Compared with other pericyte candidates, MSCs are expected to play dual roles: stabilizing engineered micro vessels and performing their stem cell functions after implantation. In this mini review, we discuss important considerations for successful MSC-EC co-cultures to achieve a robust vascular network.…”