Harnessing developmental processes for vascular engineering and regeneration

Abstract

The formation of vasculature is essential for tissue maintenance and regeneration. During development, the vasculature forms via the dual processes of vasculogenesis and angiogenesis, and is regulated at multiple levels: from transcriptional hierarchies and protein interactions to inputs from the extracellular environment. Understanding how vascular formation is coordinated in vivo can offer valuable insights into engineering approaches for therapeutic vascularization and angiogenesis, whether by creating new vasculature in vitro or by stimulating neovascularization in vivo. In this Review, we will discuss how the process of vascular development can be used to guide approaches to engineering vasculature. Specifically, we will focus on some of the recently reported approaches to stimulate therapeutic angiogenesis by recreating the embryonic vascular microenvironment using biomaterials for vascular engineering and regeneration.

Keywords: Angiogenesis; Biomaterials; Stem cells; Tissue engineering; Vasculogenesis.

Fig. 1.

Schematic representation of vasculogenesis and angiogenesis. (A) During vasculogenesis, the mesoderm-derived endothelial cells (ECs) migrate and form lumen structures, a process mediated via the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling pathway. Platelet-derived growth factor (PDGF) secretion by ECs recruits nearby mesenchymal stem cells (MSCs), which in turn release ANG1 (angiopoietin 1). Release of ANG1 stimulates mural coverage and basement membrane deposition, which in turn promotes vessel tightness via the ANG1/TIE2 (endothelial-specific receptor tyrosine kinase; TEK) signaling system. Transforming growth factor β (TGFβ) is activated through the interaction of ECs and MSCs, which induces mural cell differentiation and inhibits EC proliferation. Finally, the vessel is covered with perivascular cells. (B) Angiogenesis occurs when a quiescent vessel of the existing vasculature undergoes sprouting, elongation and lumen formation to create new vessels. Pro-angiogenic factors, such as basic fibroblast growth factor (bFGF) and VEGF, stimulate initial EC sprouting before perivascular cells stabilize the nascent vessel to establish a perfusable de novo blood vessel. α_v, β₃, a type of integrin; ECM, extracellular matrix; PDGFBB, platelet-derived growth factor subunit B homodimer;

Fig. 2.

Engineered vascular network from pluripotent stem cells within a hyaluronic acid hydrogel matrix. (A) Human pluripotent stem cells (PSCs) differentiate into bipotential early vascular cells (EVCs; i) that can mature into functional endothelial cells (ECs) and perivascular cells (ii) when placed within a synthetic hyaluronic acid (HA) hydrogel. The HA hydrogel supports the self-organization and differentiation of the bipotential EVCs into a vascular network. (B) PSC-derived EVCs self-assemble into networks in HA hydrogels (i). Multilayered structures can be detected (ii), as demonstrated by 3D projection images of NG2 (green) and phalloidin (red), and by nuclei (blue) showing NG2+ perivascular cells integrated into hollow structures. Adapted, with permission, from Kusuma et al. (2013). Scale bars: 50 μm. CD31, cluster of differentiation 31; CD105, cluster of differentiation 105; CD146, cluster of differentiation 146; DAPI, 4′,6-diamidino-2-phenylindole; MMP, matrix metalloproteinase; NG2, neural/glial antigen 2; PDGFRβ, platelet-derived growth factor receptor β; VEcad, VE-cadherin.