How Tissue Engineering Became The Field of Regenerative Medicine

During the last two decades, tissue engineering has becomes a rapidly growing field of regenerative medicine. In general, tissue engineering mainly focuses on the combination of cells, biomaterials, and suitable biochemical and physicochemical factors to constitute a tissue-like functional construct to restore or improve damaged tissues or whole organs. However, the application of this approach in clinical treatment is still restricted by the failure to meet the required size of the engineered construct. This key boundary is due to the death of the encapsulated cells in a hypoxic environment after implantation.

Because the diffusion capacity of oxygen is very limited, it allows only cells within 100–200 μm from the nearest capillary to survive. For an implanted 3D structure with dimensions greater than a few hundred micrometers, only the cell on the surface may reach the oxygen source, while most of the encapsulated cells inside the scaffold would not survive after one week. AccordinglyThus, the establishment of an in vitro functional internal vascular network is widely considered as the most potential solution to increase the size of the engineered construct used in clinical treatments.

It is well known that endothelial cells (ECs) line the entire vascular system, from the largest arteries to the smallest capillaries. ECs haves been widely investigated as vascularizing cells to generate of microvasculature network in a tissue construct in vitro to shorten avascular conditions post-implantation. To optimize vascularization strategies, it is essential to understand and predict the interactions between ECs and material, as well as ECs and other cell types, such as pericytes, stem cells, and immune cells.

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Although there are plenty studies focused on this issue, current knowledge about ECs and their capacity is still poorly understood due to the complexity and heterogeneity of ECs. ECs can be extracted from different organs and tissues, and these cells vary in term of morphology, gene expression, growth factor release profile, angiogenic potential, and regulator function. In 2003, Chi et al. performed DNA microarrays of 53 cultured ECs from in different types of blood vessels and different anatomic locations.

Hierarchical cluster analysis of gene expression patterns from 28 large vessels derived ECs and 25 microvascular derived ECs revealed that there is a ubiquitous distinction between these two EC types, especially the ECM interaction, neuronal signaling, migration, angiogenesis, and lipid metabolism. Furthermore, significance analysis of microarrays proved that ECs from different organs had distinct, intrinsic gene expressions, and could be considered as distinct cell types. Nevertheless, the review of Rafii on the endothelial angiocrine profile shows that different organ-specific ECs can release different factors to maintain that organ’s homeostasis, regulate its regeneration, and balance the self-renewal and differentiation of the nearby stem cells. Rafii emphasized that using ECs extracted from the same organ/tissue that needs to be regenerated can release specific angiocrine factors which induce organ-featured signaling pathway to enhance the regeneration and improve the function of the damaged tissue.

However, this heterogeneity has been overlooked in most of the studies of pre-vascularization. HUVECs, which may be not the most appropriate cell types in many applications, are still wildly used because they are easy to obtain, maintain, and handle. Until 2016, more than 80% of studies of vascularization in the biomaterial field used human pulmonary artery ECs (HUVECs) and endothelial progenitor cells (EPCs) instead of the targeted organ-specific ECs. Thereupon the regeneration and regulation function of the organ-specific ECs has not been fully exploited. The present review aims to provide an overview of the endothelial cell heterogeneity, focuses on the in vitro instructive and inductive contribution of organ-specific ECs to other cell types, especially stem cells and pericytes. Following, the use of organ-specific ECs in different tissue models is summarized and reported.