Mesenchymal stem cells for pre-vascularization of engineered tissues

Recent advances in the field of stem cell biology and tissue engineering have revolutionized therapeutic approaches to treat various diseases, especially chronic wounds, bone diseases, cardiovascular complications, and neurodegenerative diseases. Different stem cell types have been investigated for designing appropriate therapeutic treatments. Among them, approaches involving embryonic and induced pluripotent stem cells (iPSCs) are ethically and socially controversial. In addition, these stem cell types, due to their high pluripotency, contain risks of teratoma formation.1,2 In the past decade, mesenchymal stem cells (MSCs) have attracted considerable attention due to their straightforward and less invasive isolation procedure as well as their multi-differentiation potential. MSCs can differentiate into various cell types including osteoblasts, chondrocytes, adipocytes, smooth muscle like cells, endothelial like cells and cardiomyocyte like cells. Moreover, being immunoprivileged, allogenic MSCs encounter minimal risk of immune rejection. They also secrete various trophic factors, which can promote cell survival and tissue regeneration.3,4 These promising capabilities have made MSCs potential candidate for construction of various tissue-engineered products. Nevertheless, engineered tissues with a thickness larger than 150μm require a functional micro vascular network to supply gases, nutrients, metabolic byproducts, and integrate with host vasculature after implantation.5 In the physiological capillary structure, endothelial cells (ECs) surround the vessel lumen. These ECs are themselves wrapped by pericytes, which stabilize the capillary structure.6 Numerous studies have confirmed that MSCs can function as pericytes.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.9‒12 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. These considerations include an appropriate cell source, cell-seeding order, optimum oxygen (O2) levels, appropriate extracellular matrix (ECM) and tissue scaffold features (Figure 1). Figure 1 Considerations for MSC-EC co-culture for development of prevascularized engineered tissues. (A) Various sources from which MSCs can be isolated, (B) MSCs can be cultured on preformed vascular networks formed by ECs. In contrast, ECs cultured on MSC sheet forms better vascular networks, (C) MSCs maintain stemness and increase angiogenic growth factor secretion in a hypoxic environment. Whereas, ECs prefer normoxic environment for cell survival, proliferation and development of vascular networks, (D) Various natural and synthetic materials support MSC-EC co-culture. Decellularized ECM promotes development of robust vascular networks.