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Abstract
The vasculature is an essential, physiological element in virtually all human tissues. Formation of perfusable vasculature is therefore crucial for reliable tissue modeling. Three-dimensional vascular networks can be formed through the co-culture of endothelial cells (ECs) with stromal cells embedded in hydrogel. Mesenchymal stem/stromal cells (MSCs) derived from bone marrow (BMSCs) and adipose tissue (ASCs) are an attractive choice as stromal cells due to their natural perivascular localization and ability to support formation of mature and stable microvessels in vitro. So far, BMSCs and ASCs have been compared as vasculature-supporting cells in static cultures. In this study, BMSCs and ASCs were co-cultured with endothelial cells in a fibrin hydrogel in a perfusable microfluidic chip. We demonstrated that using MSCs of different origin resulted in vascular networks with distinct phenotypes. Both types of MSCs supported formation of mature and interconnected microvascular networks-on-a-chip. However, BMSCs induced formation of fully perfusable microvasculature with larger vessel area and length whereas ASCs resulted in partially perfusable microvascular networks. Immunostainings revealed that BMSCs outperformed ASCs in pericytic characteristics. Moreover, co-culture with BMSCs resulted in significantly higher expression levels of endothelial and pericyte-specific genes, as well as genes involved in vasculature maturation. Overall, our study provides valuable knowledge on the properties of MSCs as vasculature-supporting cells and highlights the importance of choosing the application-specific stromal cell source for vascularized organotypic models.
Highlights
Microvascular networks are fundamental elements of almost every human tissue
We examined two types of human primary Mesenchymal stem/ stromal cells (MSCs)—bone marrowderived mesenchymal stem/stromal cells (BMSCs) and adipose tissue-derived mesenchymal stem/stromal cells (ASCs), for their ability to support microvascular network formation and maturation in fibrin matrix and act as perivascular cells when co-cultured with endothelial cells (ECs) in a microfluidic chip environment
We examined morphological characteristics including 3D structure, lumen-containing vessel formation, basement membrane deposition, EC-EC cell junctions of the microvascular networks formed by EC-BMSC and EC-ASC co-cultures
Summary
Microvascular networks are fundamental elements of almost every human tissue. The vascular system is responsible for the delivery of oxygen and nutrients and removal of waste products. Current approaches for in vitro vascularization mimic the process of in vivo vasculogenesis and angiogenesis by exploiting the intrinsic ability of ECs to self-organize into vessel-like structures and to create new vessels from pre-existing ones (Chen et al, 2013; Jeon et al, 2014; Jusoh et al, 2015; Guo et al, 2019; Li et al, 2019) While these approaches have proven successful for particular applications, most of them suffer from the lack of supportive mural cells that are fundamental elements of physiological vasculature (Sweeney and Foldes 2018). The aforementioned approaches often fail to reproduce the structure of the vessels leading to formation of immature vascular networks and require the use of multiple angiogenic growth factors to promote the neovessel formation and maintain stability of the vasculature (Whisler et al, 2014)
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