Although recent data suggests that osteoblasts play a key role within the hematopoietic stem cell (HSC) niche, the mechanisms underpinning this remain to be fully defined. The studies described herein examine the role in hematopoiesis of Osteopontin (Opn), a multidomain, phosphorylated glycoprotein, synthesized by osteoblasts, with well-described roles in cell adhesion, inflammatory responses, angiogenesis, and tumor metastasis. We demonstrate a previously unrecognized
IntroductionHematopoietic stem cell (HSC) engraftment is a multistep process, involving homing, transmarrow migration (TMM), and lodgment within a bone marrow (BM) niche. Homing is the specific recruitment of HSCs to the BM and involves the recognition of HSCs by the BM microvascular endothelium and transendothelial cell migration into the hematopoietic space. Lodgment is defined as the selective migration of HSCs to a suitable niche within the extravascular compartment. In comparison to homing, very little is known about molecules that regulate HSC lodgment and, moreover, the retention of HSCs within these distinct anatomical locations.In accord with the stem cell niche model proposed by Schofield, 1 recent studies within our laboratory demonstrate that HSCs actively migrate toward and reside within the endosteal region at the bone and BM interface. 2,3 This concept is supported by studies reported by Calvi et al, 4 Zhang et al, 5 and Arai et al, 6 which highlight the importance of direct contact and interactions between HSCs and osteoblasts at the endosteal surface in the regulation of HSC proliferation. Further evidence that osteoblasts directly regulate hematopoiesis is provided by studies in which conditional ablation of osteoblasts results in significant reduction of marrow hematopoiesis, 7 although the factors responsible for this profound effect remain to be determined. In addition, in vitro evidence indicates that osteoblastic cells can expand HSC numbers 8 and, when cotransplanted with HSCs, can improve engraftment. 9 Collectively, these findings suggest that osteoblasts are a key cell type within the HSC niche and that molecules expressed by these cells may have previously unrecognized roles in regulating hematopoiesis.One molecule that shows high levels of expression in osteoblasts cells lining bone trabeculae is Osteopontin (Opn), 10 an observation that is not unexpected given its well-described role as a key regulator of bone homeostasis. 11 Opn is a multidomain, phosphorylated glycoprotein synthesized by many cell types and involved in many physiologic and pathologic processes, including cell adhesion, 12 angiogenesis, 13 apoptosis, inflammatory responses, and tumor metastasis. 14 Physiologically, phosphorylation, glycosylation, and cleavage of Opn result in molecular mass variants, ranging from 25 to 75 kDa. The different effects that Opn elicit are attributable to its multiple receptors, binding sites, and its various forms. 15 One of the major serine proteases to cleave Opn is thrombin, giving rise to a 24-kDa and a 45-kDa fragm...
