Hematopoietic stem and progenitor cell trafficking

Abstract

Migration of hematopoietic stem cells (HSCs) is essential during embryonic development and throughout adult life. During embryogenesis, trafficking of HSCs is responsible for the sequential colonization of different hematopoietic organs by blood-producing cells. In adulthood, circulation of HSCs maintains homeostasis of the hematopoietic system and participates in innate immune responses. HSC trafficking is also crucial in clinical settings such as bone marrow (BM) and stem cell transplantation. This review provides an overview of the molecular and cellular signals that control and fine-tune trafficking of HSCs and hematopoietic progenitor cells in embryogenesis and during postnatal life. We also discuss the potential clinical utility of therapeutic approaches to modulate HSC trafficking in patients.

Figure 1. Trafficking of hematopoietic stem and progenitor cells in fetal life and during adulthood

Left panel: fetal HSPCs are originated in yolk sac and migrate to AGM region and placenta. Alternatively, placental HSPCs are originated de novo. Very soon after that, HSPCs from early embryonic hematopoietic sites colonize fetal liver, which becomes the main hematopoietic organ during fetal development. Subsequently, fetal liver emigrants inhabit thymus, spleen and BM. BM becomes the main organ of adult HSPC development (right panel). The majority of HSPCs reside in the BM where they undergo self-renewal and give rise to differentiated hematopoietic cells. However, some HSPCs continuously leave the marrow and enter the blood. Circulating HSPCs either return to the BM or migrate to peripheral organs, which they exit via lymphatics. The major lymph vessel in the body, thoracic duct, drains into venous circulation, therefore HSPCs can reach BM from periphery via blood. Spl – spleen, numbers in parenthesis – day of gestation when a fetal organ is colonized with HSPC.

Figure 2. Migration of hematopoietic stem and progenitor cells within BM

HSPCs enter the BM through sinusoids, which constitutively express traffic molecules that support unique a multistep cascade for HSPC homing. First, circulating HSPCs tether to the vessel wall by engaging vascular selectins, P- and E-selectin, which bind to carbohydrate ligands that are associated with PSGL-1 and/or CD44 (HCELL) on HSPCs Tethered cells then roll slowly engaging both endothelial selectins and the integrin α4β1-VCAM-1 pathway. Some studies have also implicated α4β7 –MAdCAM-1 in the rolling step. The rolling HSPCs are then activated by the chemokine CXCL12, which signals through CXCR4. The chemokine signal induces a conformational change in α4β1 (α4β1*) resulting in increased affinity for VCAM-1, which mediates firm arrest. Next, the adherent HSPCs transmigrate through the vessel wall following extracellular chemoattractants (possibly CXCL12) that signal through G-protein-coupled receptors. Extravascular trafficking allows HSPCs to lodge in specific niches, represented by various stromal cells (fibroblasts, osteoblasts, osteoclasts and adipocytes). Stromal cells maintain the prerequisite conditions for HSPC survival and function in the BM. HSPC retention in niches is mediated by interactions of α4β1 with VCAM-1 and fibronectin (Fn) (the later also interacts with another β1 integrin – α5β1), and β2 integrins with ICAM-1, CXCR4 with CXCL12 and cKit with its ligand (KitL). Retention also involves the Ca²⁺ receptor (CaR), a member of the large G-protein-coupled receptor family, and homotypic adhesion via N-cadherin. In both homeostatic and stress-induced conditions, some BM-resident HSPCs undergo de-adhere and leave the BM (a process known as “mobilization”). HSPC mobilization involves up-regulation of proteolytic enzymes (matrix metalloptroteinase 9, cysteine protease cathepsin K, dipeptidase CD26), which leads to cleavage of CXCL12, KitL and VCAM-1. As a result, HSPCs can detach from the BM stromal cells and enter the circulation.

Figure 3. Migration of HSPCs within peripheral tissues

Blood-borne HSPCs have the capacity to enter peripheral non-hematopoietic tissues from the blood. The mechanisms that control this process are still poorly understood. In the organs, some HSPCs can spontaneously differentiate into immune cells (option 1). This differentiation dramatically increases under stress conditions (such as infection or tissue necrosis), since HSPCs receive signals via toll-like receptors (TLRs) that promote myeloid differentiation (option 2). HSPCs that do not undergo differentiation spend ~48h within peripheral tissues before they access local draining lymphatics (option 3), a migration step that depends on sphingosine-1-phosphate (S1P) and S1P receptor 1 (S1P1). The free S1P level is high in the lymph but low in tissues owing to constant degradation of S1P in the latter by S1P lyase. When HSPCs follow the S1P gradient and enter the lymph, they return to the circulation to can either access the BM or home into another peripheral tissue.