How do stem cells find their way home?

Abstract

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) , IntroductionThe hallmark of hematopoietic stem cells (HSCs) is their migration and repopulation potential (self-renewal and multilineage differentiation capacities). Progenitors isolated from the murine embryo, which lack directional migration and homing in adult mice that received transplants, are nondefinitive, cannot engraft the bone marrow (BM), and fail to rescue lethally irradiated recipients. These progenitors require in vitro stimulation with stromal cells, which convert them into functional, BM-repopulating stem cells endowed with migration and homing potential. 1 Interestingly, migration of mobilized human CD34 ϩ cells toward a gradient of the chemokine stromal derived factor-1 (SDF-1) in vitro correlates with their in vivo repopulation potential in patients who received autologous transplants and in immune-deficient nonobese diabetic/ severe combined immunodeficient (NOD/SCID) mice. [2][3][4] Most clinical and experimental stem cell transplantation protocols use intravenous (iv) injections of recipients previously conditioned with DNA-damaging agents such as total body irradiation (TBI) and/or chemotherapy. These agents induce massive cell death of cycling hematopoietic cells in the bone marrow, spleen, and blood and damage the physiological BM endothelium barrier. Tissue damage leads to a dramatic increase in the levels of secreted chemokines, cytokines, and proteolytic enzymes in many organs as part of the regeneration and repair process, which have profound impacts on stem cell migration and repopulation. DNA damage and stress also lead to proliferation and mobilization of quiescent stem cells from the BM to the circulation (reviewed in Cottler-Fox et al 5 ). For example, cyclophosphamide is used clinically to induce stem cell mobilization and to destroy malignant cells prior to stem cell transplantation. Yet, DNA damage aimed at eliminating malignant cells in patients also increases secretion of survival, migration, and angiogenic factors such as SDF-1. This chemokine can increase CXC chemokine receptor 4 ϩ (CXCR4 ϩ ) malignant stem cell survival, proliferation, invasion, and metastasis, leading to the spreading of tumors in a broad range of cancers including breast, prostate, and brain tumors as well as leukemias. [6][7][8][9] Interact...

CD44 in hematological neoplasias

“…Differentiation and proliferation of HSC is closely connected to the microenvironment. Therefore they are dependent on finding their specific niche in the BM [99,100]. Together with observed eradication of LIC and reduced repopulation in immune deficient mice [101], this might provide a way of antibody-triggered, CD44-and IL-8/GM-CSF-mediated targeting of AML cells via combined effect of reversed differentiation block and dependency of LIC on their bone marrow niche.…”

Homing of Cancer Cells to the Bone

“…G-CSF and AMD3100, a small molecule inhibitor of CXCR4, both inhibit the SDF-1/CXCR4 axis and lead to mobilization of HSCs [188][189][190]. In animal models, AMD1300 treatment increases mobilization of myeloma cells into the circulation and increases their sensitivity to bortezomib [191].…”

Stem cells: novel players in the treatment of erectile dysfunction

“…58 More specifically, certain types of stem cells have been shown to express mRNA and a large number of chemokine-receptors. Various groups have shown expression of the chemokine stromal cell-derived factor 1a (CXCL12) in myocardial infarction; 59 CX3CL1, CCL2, CCL3 and CCL5 in peripheral neural injury; 60 and CCL7 in rat models of birth injury and stress urinary incontinence. 61 Recent data indicate that CXCL12 may play a role in trafficking ADSCs towards the major pelvic ganglion in rats with an injured cavernous nerve.…”

“…[58][59][60][61][62][63] Rolling and firm adhesion is followed by transendothelial migration across the physical endothelium/extracellular matrix barrier.…”

“…In the last stage, stem cells finalize their 'homing' by anchorage to their specialized niches in the extravascular space of the endosteum region and at perivascular sites. 60 Reawakening and mobilisation of endogenous stem cells The development of techniques to reawaken and mobilize endogenous pools of stem cells would represent progress in the field of regenerative medicine. In general, the recruitment of HSCs from bone marrow into blood is termed 'mobilisation'.…”