Patients undergoing chemotherapy for hematologic malignancies frequently ask, “How do hematopoietic stem cells (HSCs) recover after treatment so that the blood counts return to normal?” The clinician usually describes how quiescent HSCs can robustly awaken to reconstitute red cells, white cells, and platelets and simultaneously self-renew, creating another quiescent HSC. This process provides a mechanism for both expansion of hematopoiesis and self-renewal of the quiescent HSC pool, assuring maintenance of hematopoiesis. The majority of adult HSCs are quiescent, maintained in the G0 phase of the cell cycle, and in this dormant state, stem cells are protected against myelotoxic agents such as chemotherapy or radiation. Once the toxic insult is obviated, the quiescent stem cell pool is activated and reconstitution of hematopoiesis ensues.1 HSC preservation occurs in specialized niches in the vascular/endothelial and osteoblastic/endosteal bone marrow microenvironment. Multiple cell-cell adhesive interactions with specific molecular receptors, cytokines, and ligands are required to ensure HSC multi-potentiality, quiescence, and selfrenewal. In the current paper, Winkler and colleagues from Mater Medical Research Institute, South Brisbane, Queensland, Australia, report that the endothelial-specific adhesion molecule, E-selectin, regulates HSC dormancy, self-renewal, and chemoresistance and suggests that hematopoietic recovery following chemotherapy could be modulated through E-selectin blockade.
E-selectin is a member of the selectin family (P-selectin and L-selectin are the other members) of cell adhesion molecules that function as lectins (proteins that bind carbohydrates). E-selectin is expressed by cytokine-activated endothelial cells, whereas P-selectin is expressed by both platelets and endothelial cells, and L-selectin is expressed by leukocytes. The investigators used wild-type and E-selectin knockout mice (Sele-/-) to show that the HSC cycle is slower when E-selectin is absent. This observation was E-selectin-specific as the HSC cycle time of P-selectin knockout mice was similar to that of their wild-type counterparts. Slower cycling suggests quiescence, and this interpretation was supported by repopulation assays in mice treated with hydroxyurea, an S-phase-specific agent. Those experiments showed that Sele-/- mice had six-fold more surviving HSCs in long-term culture assays following treatment with hydroxyurea. Despite this qualitative difference, the total number of HSCs per femur was not significantly different between Sele-/-mice and wild-type mice. HSC proliferation induced by E-selectin is mediated exclusively by vascular endothelial cells in the bone marrow, particularly those in the endosteal region compared with the central bone marrow. HSCs of Sele-/- mice withstood repeated rounds of cyclophosphamide chemotherapy significantly better than those of wild-type mice, and, compared with control mice, peripheral leukocyte counts were found to recover faster in irradiated Sele-/- animals. An E-selectin antagonist, GMI-1070, increased HSC chemo-resistance, quiescence, and self-renewal capacity without affecting the total HSC number. The effects of E-selectin appear to be mediated through binding of ligands that are expressed by HSC, including ESL-1 and glycosphingolipids, but not by the canonical E-selectin ligands PSGL-1 or CD44.
In Brief
The authors do not propose a mechanism by which E-selectin promotes HSC proliferation. A commentary by Malcolm Moore that accompanies the article hypothesizes a potential role for disruption of TGF-β mediated inhibition of HSC proliferation.2-3 Use of E-selectin antagonists could reduce the myelosuppressive effects of chemotherapy, but on a cautionary note, tumor cells appear to utilize E-selectin ligands for homing, in which case use of such antagonists may induce quiescence and chemoresistance in malignant cells.
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Competing Interests
Dr. Vercellotti indicated no relevant conflicts of interest.
