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Homing of hematopoietic stem cells (HSC) to their microenvironment niches in the bone marrow is a complex process with a critical role in repopulation of the bone marrow after transplantation. This active process allows for migration of HSC from peripheral blood and their successful anchoring in bone marrow before proliferation. The process of engraftment starts with the onset of proliferation and must, therefore, be functionally dissociated from the former process. In this overview, we analyze the characteristics of stem cells (SCs) with particular emphasis on their plasticity and ability to find their way home to the bone marrow. We also address the problem of graft failure which remains a significant contributor to morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Within this context, we discuss non-malignant and malignant hematological disorders treated with reduced-intensity conditioning regimens or grafts from human leukocyte antigen (HLA)-mismatched donors.
Biological Properties of Stem Cells
|Figure 1. Hierarchical division of the stem cell in hematopoiesis|
|Figure 2. Redefined model of hematopoiesis. Instead of a three-tiers model, through mulitipotent, oligopotent and then unilineage progenitor, the authors proposed in adult bone marrow a two-tiers scheme: a top-tier which contains multipotent cells such as HSCs and multipotent progenitors, and a bottom-tier composed of committed unipotent progenitors.|
Bone Marrow Homing
|Figure 3. Migration and homing of HSCs into the bone marrow microenvironment. E- endothelial and P- endothelial selectin were found to be important to cell movement (cell rolling) and promote weak HSC adhesion to bone marrow microvessels. The expression of the chemokine receptor CXCR4 on the HSC surface promotes cell activation via CXCL12 factor. Following stronger interaction between LFA-1/ICAM-1 and VLA-4/VCAM-1, HSCs arrest on the endothelial surface and migrate through basal lamina. The migration is also promoted by VLA-4 and VLA-5 interaction with fibronectin, present in the extracellular matrix.|
|Figure 4. Schematic representation of HSC homing. HSCs infused into blood are more responsive to stromal cell-derived factor (SDF)-1 gradient between bone marrow and blood compared to other factors that are upregulated after transplantation conditioning regimen (S1P, ATP).|
Hemopoietic Stem Cell Homing and Engraftment Defects