A novel view of the adult bone marrow stem cell hierarchy and stem cell trafficking

Abstract

This review presents a novel view and working hypothesis about the hierarchy within the adult bone marrow stem cell compartment and the still-intriguing question of whether adult bone marrow contains primitive stem cells from early embryonic development, such as cells derived from the epiblast, migrating primordial germ cells or yolk sac-derived hemangioblasts. It also presents a novel view of the mechanisms that govern stem cell mobilization and homing, with special emphasis on the role of the complement cascade as a trigger for egress of hematopoietic stem cells from bone marrow into blood as well as the emerging role of novel homing factors and priming mechanisms that support stromal-derived factor 1-mediated homing of hematopoietic stem/progenitor cells after transplantation.

Figure 1

Hypothetical relation of very small embryonic-like stem cells (VSELs) to other multi/pluripotent stem cells identified by several investigators in adult bone marrow, blood and umbilical cord blood. It is very likely that VSELs are primitive, small, dormant, stem cells that, upon proper activation, give rise to other larger multi/pluripotent stem cells identified by other investigators in hematopoietic tissues and may also give rise to hematopoietic/stem progenitor cells, mesenchymal stem cells and endothelial progenitor cells. Abbreviations: EPC, endothelial progenitor cell; HSC, hematopoietic stem cell; MASC, multipotent adult stem cells; MIAMI, marrow-isolated adult multilineage-inducible cell; MAPC, multipotent adult progenitor cell.

Figure 2

The proposed major mechanism underlying the processes of mobilization and homing of hematopoietic stem cells (HSCs). Mobilization of HSCs (upper panel). Activation of the complement cascade (ComC) is a trigger for the mobilization process. The ComC cleavage fragments C5a and _desArgC5a induce proteolytic and lypolytic enzymes from bone marrow-residing granulocytes and macrophages. These enzymes attenuate SDF-1–CXCR4- and VCAM-1–VLA-4-mediated retention of HSCs in bone marrow niches. An increase in the ComC cleavage fragments C5a and _desArgC5a in BM sinusoids chemoattracts leukocytes and monocytes from BM into PB, and these cells are the first to egress from the BM microenvironment and pave the way for HSPCs through the endothelial barrier. HSCs released from their niches are chemoattracted by the S1P gradient between bone marrow and blood. HO-1 is an inhibitor of ComC activation and mobilization of HSPCs. Homing of HSCs (lower panel). HSCs infused into blood respond to a gradient of SDF-1 between bone marrow and blood; however, conditioning for transplantation by chemo/radiotherapy may also upregulate other homing factors, such as S1P and ceramide-1-phosphate (C1P), and increase the level of extracellular nucleotides (ATP and UTP). In addition, LL-37 and β2-defensin released from BM stromal cells and osteoblasts increase the responsiveness of HSCs to an SDF-1 gradient by a priming mechanism.