Vascular Lineage Differentiation from Human Embryonic Stem Cells

Abstract

In the early stages of embryonic development, vessel formation occurs by a process referred to as vasculogenesis, in which mesodermally derived endothelial cell progenitors undergo de novo differentiation, expand, and coalesce to form a network of primitive tubules (1). These blood vessels are generally composed of two cell lineages: internal endothelial cells that form the channels for blood conduction, but alone cannot complete vasculogenesis; and periendothelial smooth muscle cells that protect and stabilize the fragile channels from rupture and provide hemostatic control (2). The cells that surround the endothelial channels vary throughout the blood vessel system (3). For instance, several layers of smooth muscle cells surround the large vessels close to the heart, whereas single cells (which are not joined into layers) called pericytes cover smaller, more distant vessels. In the vertebrate embryo, vasculogenesis occurs in the paraxial and lateral mesoderm, giving rise to the primordia of the heart, the dorsal aorta, and large vessels of the head, lung, and gastrointestinal system. Angiogenesis is the process that involves the maturation and remodeling of the primitive vascular plexus into a complex network of large and small vessels. Angiogenesis also leads to vascularization of initially avascular organs such as the kidney, brain, and limb buds. Angiogenesis is also required for postnatal tissue growth and throughout the adult life (e.g., during neovascularization of the endometrium during normal female cycle, during pregnancy in the placenta, and during wound healing) (4). Therefore, human vascular cells are important for developing engineered vessels for the treatment of vascular diseases (5,6),for enhancing vessel growth to areas of ischemic tissue or following cell transplantation (7)., and for regulating angiogenesis in rheumatoid arthritis, retinopathies, hemangiomas, and cancer (8,9)Moreover, endothelial cells were found to have the main role in organogenesis of the mouse embryo. Endothelial cells promoted liver organogenesis (10), induced pancreas differentiation (11),and were found to transdifferentiate into cardiac muscle under specific conditions (12).