The endothelium is capable of remarkable plasticity. In the embryo, primitive endothelial cells differentiate to acquire arterial, venous or lymphatic fates. Certain endothelial cells also undergo ...hematopoietic transition giving rise to multi-lineage hematopoietic stem and progenitors while others acquire mesenchymal properties necessary for heart development. In the adult, maintenance of differentiated endothelial state is an active process requiring constant signalling input. The failure to do so leads to the development of endothelial-to-mesenchymal transition that plays an important role in pathogenesis of a number of diseases. A better understanding of these phenotypic changes may lead to development of new therapeutic interventions.
Vascular endothelium possesses remarkable plasticity in response to cues from its surroundings, leading to great heterogeneity of endothelial cells in different vascular beds. Here the authors explain the molecular basis of endothelial plasticity during embryogenesis and in various diseases.
Embryonic definitive hematopoiesis generates hematopoietic stem and progenitor cells (HSPCs) essential for establishment and maintenance of the adult blood system. This process requires the ...specification of a subset of vascular endothelial cells to become blood-forming, or hemogenic, and the subsequent endothelial-to-hematopoietic transition to generate HSPCs therefrom. The mechanisms that regulate these processes are under intensive investigation, as their recapitulation in vitro from human pluripotent stem cells has the potential to generate autologous HSPCs for clinical applications. In this review, we provide an overview of hemogenic endothelial cell development and highlight the molecular events that govern hemogenic specification of vascular endothelial cells and the generation of multilineage HSPCs from hemogenic endothelium. We also discuss the impact of hemogenic endothelial cell development on adult hematopoiesis.
The formation and remodeling of a functional circulatory system is critical for sustaining prenatal and postnatal life. During embryogenesis, newly differentiated endothelial cells require further ...specification to create the unique features of distinct vessel subtypes needed to support tissue morphogenesis. In this review, we explore signaling pathways and transcriptional regulators that modulate endothelial cell differentiation and specification, as well as applications of these processes to stem cell biology and regenerative medicine. We also summarize recent technical advances, including the growing utilization of single-cell sequencing to study vascular heterogeneity and development.
Hemogenic endothelium is a specialized subset of developing vascular endothelium that acquires hematopoietic potential and can give rise to multilineage hematopoietic stem and progenitor cells during ...a narrow developmental window in tissues such as the extraembryonic yolk sac and embryonic aorta-gonad-mesonephros. Herein, we review current knowledge about the historical and developmental origins of hemogenic endothelium, the molecular events that govern hemogenic specification of vascular endothelial cells, the generation of multilineage hematopoietic stem and progenitor cells from hemogenic endothelium, and the potential for translational applications of knowledge gained from further study of these processes.
During embryonic development, multilineage HSCs/progenitor cells are derived from specialized endothelial cells, termed hemogenic endothelium, within the yolk sac, placenta, and aorta. Whether ...hemogenic endothelial cells contribute to blood cell development at other sites of definitive hematopoiesis, such as in the fetal liver and fetal bone marrow, is not known. Also unknown is whether such cells exist within the vasculature of adult bone marrow and generate hematopoietic stem cells after birth. These issues and their clinical relevance are discussed herein.
Tissue-resident macrophages have been associated with important and diverse biological processes such as native immunity, tissue homeostasis and angiogenesis during development and postnatally. Thus, ...it is critical to understand the origins and functions of tissue-resident macrophages, as well as mechanisms underlying their regulation. It is now well accepted that murine macrophages are produced during three consecutive waves of hematopoietic development. The first wave of macrophage formation takes place during primitive hematopoiesis, which occurs in the yolk sac, and gives rise to primitive erythroid, megakaryocyte and macrophage progenitors. These "primitive" macrophage progenitors ultimately give rise to microglia in the adult brain. The second wave, which also occurs in the yolk sac, generates multipotent erythro-myeloid progenitors (EMP), which give rise to tissue-resident macrophages. Tissue-resident macrophages derived from EMP reside in diverse niches of different tissues except the brain, and demonstrate tissue-specific functions therein. The third wave of macrophages derives from hematopoietic stem cells (HSC) that are formed in the aorta-gonad-mesonephros (AGM) region of the embryo and migrate to, and colonize, the fetal liver. These HSC-derived macrophages are a long-lived pool that will last throughout adulthood. In this review, we discuss the developmental origins of tissue-resident macrophages, their molecular regulation in specific tissues, and their impact on embryonic development and postnatal homeostasis.
The circulatory system is the first organ system to develop in the vertebrate embryo and is critical throughout gestation for the delivery of oxygen and nutrients to, as well as removal of metabolic ...waste products from, growing tissues. Endothelial cells, which constitute the luminal layer of all blood and lymphatic vessels, emerge de novo from the mesoderm in a process known as vasculogenesis. The vascular plexus that is initially formed is then remodeled and refined via proliferation, migration, and sprouting of endothelial cells to form new vessels from preexisting ones during angiogenesis. Mural cells are also recruited by endothelial cells to form the surrounding vessel wall. During this vascular remodeling process, primordial endothelial cells are specialized to acquire arterial, venous, and blood-forming hemogenic phenotypes and functions. A subset of venous endothelium is also specialized to become lymphatic endothelium later in development. The specialization of all endothelial cell subtypes requires extrinsic signals and intrinsic regulatory events, which will be discussed in this review.
There are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and ...soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling distinct functions. All vessels are composed of an inner layer of endothelial cells that are in direct contact with the circulating fluid; therefore, they are the first responders to circulating factors. However, endothelial cells are not homogenous; rather, they are a heterogenous population of specialized cells perfectly designed for the physiological demands of the vessel they constitute. This review provides an overview of the current knowledge of the specification of arterial, venous, capillary, and lymphatic endothelial cell identities during vascular development. We also discuss how the dysregulation of these processes can lead to vascular malformations, and therapeutic approaches that have been developed for their treatment.
Establishment of a functional vascular network is rate-limiting in embryonic development, tissue repair and engineering. During blood vessel formation, newly generated endothelial cells rapidly ...expand into primitive plexi that undergo vascular remodeling into circulatory networks, requiring coordinated growth inhibition and arterial-venous specification. Whether the mechanisms controlling endothelial cell cycle arrest and acquisition of specialized phenotypes are interdependent is unknown. Here we demonstrate that fluid shear stress, at arterial flow magnitudes, maximally activates NOTCH signaling, which upregulates GJA4 (commonly, Cx37) and downstream cell cycle inhibitor CDKN1B (p27). Blockade of any of these steps causes hyperproliferation and loss of arterial specification. Re-expression of GJA4 or CDKN1B, or chemical cell cycle inhibition, restores endothelial growth control and arterial gene expression. Thus, we elucidate a mechanochemical pathway in which arterial shear activates a NOTCH-GJA4-CDKN1B axis that promotes endothelial cell cycle arrest to enable arterial gene expression. These insights will guide vascular regeneration and engineering.
PDF
