Migration of hematopoietic stem cells through the blood, across the endothelial vasculature to different organs and to their bone marrow (BM) niches, requires active navigation, a process termed homing. Homing is a rapid process and is the first and essential step in clinical stem cell transplantation. Similarly, homing is required for seeding of the fetal BM by hematopoietic progenitors during development. Homing has physiological roles in adult BM homeostasis, which are amplified during stress-induced recruitment of leukocytes from the BM reservoir and during stem cell mobilization, as part of host defense and repair. Homing is thought to be a coordinated, multistep process, which involves signaling by stromal-derived factor 1 (SDF-1) and stem cell factor (SCF), activation of lymphocyte function–associated antigen 1 (LFA-1), very late antigen 4/5 (VLA-4/5) and CD44, cytoskeleton rearrangement, membrane type 1 (MT1)–matrix metalloproteinase (MMP) activation and secretion of MMP2/9. Rolling and firm adhesion of progenitors to endothelial cells in small marrow sinusoids under blood flow is followed by trans-endothelial migration across the physical endothelium/extracellular matrix (ECM) barrier. Stem cells finalize their homing uniquely, by selective access and anchorage to their specialized niches in the extravascular space of the endosteum region and in periarterial sites. This review is focused on mechanisms and key regulators of human stem cell homing to the BM in experimental animal models and clinical transplantation protocols.

The chemokine stromal-derived factor-1 (SDF-1) controls many aspects of stem cell function. Details of its regulation and sites of production are currently unknown. We report that in the bone marrow, SDF-1 is produced mainly by immature osteoblasts and endothelial cells. Conditioning with DNA-damaging agents (ionizing irradiation, cyclophosphamide, and 5-fluorouracil) caused an increase in SDF-1 expression and in CXCR4-dependent homing and repopulation by human stem cells transplanted into NOD/SCID mice. Our findings suggest that immature osteoblasts and endothelial cells control stem cell homing, retention, and repopulation by secreting SDF-1, which also participates in host defense responses to DNA damage.

Significance: Blood forming, hematopoietic stem cells (HSCs) mostly reside in the bone marrow in a quiescent, nonmotile state via adhesion interactions with stromal cells and macrophages. Quiescent, proliferating, and differentiating stem cells have different metabolism, and accordingly different amounts of intracellular reactive oxygen species (ROS). Importantly, ROS is not just a byproduct of metabolism, but also plays a role in stem cell state and function. Recent Advances: ROS levels are dynamic and reversibly dictate enhanced cycling and myeloid bias in ROS ^high short-term repopulating stem cells, and ROS ^low quiescent long-term repopulating stem cells. Low levels of ROS, regulated by intrinsic factors such as cell respiration or nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) activity, or extrinsic factors such as stem cell factor or prostaglandin E2 are required for maintaining stem cell self-renewal. High ROS levels, due to stress and inflammation, induce stem cell differentiation and enhanced motility. Critical Issues: Stem cells need to be protected from high ROS levels to avoid stem cell exhaustion, insufficient host immunity, and leukemic transformation that may occur during chronic inflammation. However, continuous low ROS production will lead to lack of stem cell function and opportunistic infections. Ultimately, balanced ROS levels are crucial for maintaining the small stem cell pool and host immunity, both in homeostasis and during stress situations. Future Directions: Deciphering the signaling pathway of ROS in HSC will provide a better understanding of ROS roles in switching HSC from quiescence to activation and vice versa, and will also shed light on the possible roles of ROS in leukemia initiation and development. Antioxid. Redox Signal. 21, 1605–1619.