Reactive oxygen species regulate hematopoietic stem cell self-renewal, migration and development, as well as their bone marrow microenvironment

Abstract

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.

FIG. 1.

Intracellular reactive oxygen species (ROS) regulate self renewal versus activation of hematopoietic stem cells (HSCs). Quiescent, long-term repopulating stem cells are characterized by low levels of ROS. Elevation of ROS levels in the stem cells would enhance cycling and motility of the stem cells and provide short-term repopulation ability. The high levels of ROS are reversible and reduction of ROS levels in the stem cell would induce reduced cycling and restore long-term repopulation potential. Excess of ROS, on the other hand, would lead to senescence and apoptosis that cannot be rescued.

FIG. 2.

Environmental factors maintain low ROS levels in the stem cells to maintain the stem cell pool. The mesenchymal stromal cells and α-smooth muscle actin (αSMA)⁺ macrophages act together to preserve low ROS levels in HSCs. The αSMA⁺ macrophage contains cyclooxygenase-2 (COX-2) that produces prostaglandin E2 (PGE2) (1), which is secreted to the vicinity of the stem cell (2) and reduces its intracellular ROS levels. PGE2 also promotes CXCL12 production from the mesenchymal stromal cell (3). In addition, the stem cells are connected to the mesenchymal stromal cells via connexin gap junctions that transfer ROS from the stem cell to the mesenchymal stem cell (4) and contribute to the reduction of ROS levels in the stem cell.

FIG. 3.

Cell intrinsic factors maintain low ROS levels to prevent stem cell pool exhaustion. Under hypoxic conditions, the transcription factors HIF-1α, FOXO3, and ATM play a crucial role in mediating intracellular ROS levels and stem cell maintenance in a p16 and BID- and AKT-dependent manner. The low ROS levels maintained in the stem cell protect the stem cell pool from exhaustion by limiting over proliferation and differentiation of the stem cells. ATM, ataxia telangiectasia mutated; FOXO3, forkhead box protein O3; HIF-1α, hypoxia-inducible factor 1-α.

FIG. 4.

HIF-1α and ROS levels are mediated by steady state versus stress conditions and modulate stem cell dormancy versus proliferation. In steady state, HIF-1α levels in the HSC are high [1] and ROS levels are low. In this state, the HSC are dormant. However, what induces the high expression of HIF-1α is not clear. Possible factors that may induce high levels of HIF-1α are hypoxia and cytokines. Under stress conditions [2], enhanced mitochondrial respiration and NADPH oxidase activity elevate ROS levels in the HSC, concomitant with a reduction in HIF-1α levels. At this stage, HSCs enter cell cycle and proliferation. [3] How ROS levels affect HIF-1α levels in the HSC is yet to be determined. NADPH oxidase, nicotinamide adenine dinucleotide phosphate-oxidase.

FIG. 5.

Elevated ROS levels in HSCs and mesenchymal stromal cells promote HSCs motility and mobilization. Hepatocyte growth factor (HGF) (1) and sphingosine 1-phosphate (S1P) (2) which bind to the hematopioietic stem cells act directly to elevate intracellular levels of ROS in HSCs that enhance their motility. S1P binding to the mesenchymal stromal cells promotes CXCL12 secretion in an ROS-dependent manner (3). CXCL12 acts as a chemoattractant to the HSCs when is secreted into the blood stream (4). In addition, elevated ROS levels, which can be triggered by S1P binding to mesenchymal stromal cells, induce matrix-metalloproteinases (MMPs) secretion (5).