Blood on the tracks: hematopoietic stem cell-endothelial cell interactions in homing and engraftment

Abstract

Cells of the hematopoietic system undergo rapid turnover. Each day, humans require the production of about one hundred billion new blood cells for proper function. Hematopoietic stem cells (HSCs) are rare cells that reside in specialized niches and are required throughout life to produce specific progenitor cells that will replenish all blood lineages. There is, however, an incomplete understanding of the molecular and physical properties that regulate HSC migration, homing, engraftment, and maintenance in the niche. Endothelial cells (ECs) are intimately associated with HSCs throughout the life of the stem cell, from the specialized endothelial cells that give rise to HSCs, to the perivascular niche endothelial cells that regulate HSC homeostasis. Recent studies have dissected the unique molecular and physical properties of the endothelial cells in the HSC vascular niche and their role in HSC biology, which may be manipulated to enhance hematopoietic stem cell transplantation therapies.

Keywords: Endothelial cell; Engraftment; Hematopoietic stem cell; Hematopoietic stem cell transplantation; Homing; Stem cell niche.

Fig. 1

Endothelial cell-HSC interactions during homing and engraftment. During development and transplantation HSCs must home to, and engraft in, the stem cell niche. a Definitive hematopoiesis is initiated when HSCs are specified from hemogenic endothelium in the aortagonad-mesonephros (AGM) region. HSCs bud from the ventral wall of the dorsal aorta, enter circulation, and home to the fetal liver. After extravasating into the fetal niche, ECs remodel around the HSC in a process termed “endothelial cell cuddling.” HSCs expand in the fetal niche and then home to, and engraft in, the adult niche in the bone marrow. HSCs engraft in complex and specialized niches consisting of multiple specialized cell types. These niches maintain HSCs and regulate their self-renewal and differentiation into all mature blood lineages. b HSCs undergo a series of stereotyped actions to home towards the niche, all of which depend on endothelial cells—rolling, arrest and firm adhesion, spreading, and extravasation. Rolling is initiated when E- and P-selectin receptors on ECs tether to their ligands on the HSC, serving as a molecular brake to slow HSC migration in circulation. Chemokine CXCL12 then activates VCAM and ICAM adhesion molecules, which promote firm adhesion of HSCs to vascular ECs. Finally, chemokines and adhesion molecules direct polarized migration across the endothelium and result in HSC extravasation

Fig. 2

Endothelial cells regulate HSC engraftment and maintenance in the adult bone marrow niche. The bone marrow niche consists of different types of blood vessels. a The vascular architecture and properties of bone marrow ECs differ between arteriolar and sinusoidal vessels. Arterioles, which have low permeability and high rates of blood flow, branch into sinusoids, which have high permeability and low rates of flow. Differences in arteriolar and vascular associated cells can be observed and may have an impact on the regulation of HSCs within these niches. Non-myelinating Schwann cells that maintain hibernating HSCs exclusively associate with arterioles, whereas megakaryocytes, that also establish a quiescent niche for HSCs localize near sinusoids. b The bone marrow perivascular niche contains numerous cell types including stromal cells, macrophages, megakaryocytes, osteoblasts and osteoclasts, sympathetic nerves, and endothelial cells. Endothelial cells play an important role in HSC maintenance, self-renewal, and differentiation, and are an important source of two key angiocrine factors, CXCL12 and SCF. Distinct subsets of endothelial cells, arterioles and sinusoids, may make up unique bone marrow stem cell niches with different properties. Arteriolar ECs have been associated with HSC retention, whereas sinusoidal ECs release factors that promote HSC proliferation, such as Kit-ligand and Notch ligands. Moreover, sinusoids are the exclusive site of HSC homing and trafficking. The difference in ROS levels between arteriolar and sinusoidal microenvironments may affect HSC cell cycle state and metabolism. Thus far, quiescent HSCs have been observed both near arteriolar and sinusoidal vessels. Nonetheless, the unique physical and molecular properties of the sinusoidal and arteriolar microenvironments may affect HSC state