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

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.

Role of microvascular endothelial cells on proliferation, migration and adhesion of hematopoietic stem cells

“…Mesenchymal stem cells (MSCs) and endothelial cells (ECs) are the two major types of cells in bone marrow niche. It has been reported that ECs provide a nutrient-rich hematopoietic niche for HSC, which can effectively promote HSC proliferation and differentiation [4][5][6][7][8][9][10].…”

Evaluation of a developmental hierarchy for breast cancer cells to assess risk-based patient selection for targeted treatment

“…Specifically, cells of the BM niche can retain BCCs in a dormant phase, making them difficult to treat. In addition, it is important to note that any treatment of BCCs within the BM microenvironment must avoid overt toxicity to the endogenous hematopoietic stem cells 27 , 30 , 31 .…”

Glutaredoxin 1 up-regulates deglutathionylation of α4 integrin and thereby restricts neutrophil mobilization from bone marrow

“…␣4 integrin seems to play few roles in this process, with controversial expression on peripheral blood neutrophils (42)(43)(44). A wide range of studies revealed that VLA-4/VCAM-1 adhesion signaling is essential in homeostatic stem cell/progenitor cell egress from the bone marrow (45,46). Although the effect of VLA-4 on neutrophil release from the bone marrow under rest condition is debated, VLA-4 has been proven to mediate marrow neutrophil mobilization under stress conditions (17,19).…”