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Review
, 44 (3), 151-164

Current Developments in Mobilization of Hematopoietic Stem and Progenitor Cells and Their Interaction With Niches in Bone Marrow

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Review

Current Developments in Mobilization of Hematopoietic Stem and Progenitor Cells and Their Interaction With Niches in Bone Marrow

Rudolf Richter et al. Transfus Med Hemother.

Abstract

The clinical application of hematopoietic stem and progenitor cells (HSPCs) has evolved from a highly experimental stage in the 1980s to a currently clinically established treatment for more than 20,000 patients annually who suffer from hematological malignancies and other severe diseases. Studies in numerous murine models have demonstrated that HSPCs reside in distinct niches within the bone marrow environment. Whereas transplanted HSPCs travel through the bloodstream and home to sites of hematopoiesis, HSPCs can be mobilized from these niches into the blood either physiologically or induced by pharmaceutical drugs. Firstly, this review aims to give a synopsis of milestones defining niches and mobilization pathways for HSPCs, including the identification of several cell types involved such as osteoblasts, adventitial reticular cells, endothelial cells, monocytic cells, and granulocytic cells. The main factors that anchor HSPCs in the niche, and/or induce their quiescence are vascular cell adhesion molecule(VCAM)-1, CD44, hematopoietic growth factors, e.g. stem cell factor (SCF) and FLT3 Ligand, chemokines including CXCL12, growth-regulated protein beta and IL-8, proteases, peptides, and other chemical transmitters such as nucleotides. In the second part of the review, we revise the current understanding of HSPC mobilization. Here, we discuss which mechanisms found to be active in HSPC mobilization correspond to the mechanisms relevant for HSPC interaction with niche cells, but also deal with other mediators and signals that target individual cell types and receptors to mobilize HSPCs. A multitude of questions remain to be addressed for a better understanding of HSPC biology and its implications for therapy, including more comprehensive concepts for regulatory circuits such as calcium homeostasis and parathormone, metabolic regulation such as by leptin, the significance of autonomic nervous system, the consequences of alteration of niches in aged patients, or the identification of more easily accessible markers to better predict the efficiency of HSPC mobilization.

Keywords: Bone marrow; Hematopoietic stem cell; Mobilization; Stem cell niche.

Figures

Fig. 1
Fig. 1
Hematopoietic stem cell niches can be provided by different cell types. The different cell types are characterized by expression of distinct molecules and are found in the endosteal, sinusoidal HSPC niche or near the small arterioles. Stromal cells in the sinusoidal niche are characterized by expression of Nestin, CD146, STRO-1, HS2, HS3, HS4. SDF-1/CXCL12, Leptin receptor. VE-cadherin(Cdh5)-expressing endothelial cells are also found in the sinusoidal niche. CAR cells are characterized by expression of high amounts of SDF-1/CXCL12. Connexin 43 and 45 expressing Nestin+ MSCs as well as osteoblasts reveal electromechanical coupling with β-adrenergic nerves. In the endosteal niche, osteoblasts and especially SNO osteoblasts as well as CAR cells were identified. NG2 expressing cells encircling small arterioles in endosteal bone marrow are associated with quiescence HSPCs.
Fig. 2
Fig. 2
Mechanisms of G-CSF induced mobilization of HSPCs. a During steady-state homeostasis, HSPCs are predominantly retained in the bone marrow niche via stromal/HSPC interactions regulated by chemokines (especially SDF-1/CXCL12) expressed by mesenchymal stromal progenitor cells, endothelial cells and osteoblasts. Chemokines induce expression of adhesion molecules VLA-4, VLA-5, and CD44. b G-CSF induces expansion of neutrophils in the bone marrow, which release proteases. These proteases inactivate chemokines, adhesion molecules and growth factors such as CXCL12, VCAM-1, and SCF. G-CSF administration depletes macrophages which suppress osteoblast function with reduced CXCL12, SCF, and VCAM-1 expression. Furthermore, G-CSF induces β3-adrenoceptor activation, which down-regulates CXCL12, SCF, and VCAM-1 expression in osteoblasts and sinusoidal stromal cells, supporting HSPC mobilization. Transiently increased concentrations of S1P and probably increased concentrations of active CXCL12 in blood plasma induce migration of HSPCs in blood. The impact of further chemotactic factors and SDF-1-CXCR4 axis priming factors has still to be elucidated.

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