There are 2 classifications of HSCs, namely, long-term and short-term. Long-term HSCs (LT-HSCs) are capable of contributing to hematopoiesis for months or even a lifetime. Short-term HSCs (ST-HSCs) have a reconstitution ability that is limited to several weeks (45, 46). LT-HSCs are maintained primarily as quiescent or slow-cycling cells, while ST-HSCs are actively cycling (47). Data from conditional inactivation of bone morphogenic protein (BMP) receptor type IA (BMPRIA) mice reveal that an increase in the number of spindle-shaped N-cadherin+CD45– osteoblastic (SNO) cells, a subset of osteoblastic lining cells, in the trabecular bone area correlates with an increase in the number of LT-HSCs, suggesting that SNO cells function as a key component of the niche to support HSCs (31) (Figure 1). Similarly, overexpression of parathyroid hormone (PTH) and PTH-related protein (PTHrP) receptor leads to increased osteoblast numbers, resulting in a parallel increase in the number of HSCs in the PTH/PTHrP receptor (PPR) transgenic mouse model (32). Both of these studies point to the dependence of LT-HSCs on the osteoblastic niche. It appears that the ability of the osteoblastic niche to retain stem cells in a quiescent state is an important mechanism in maintaining sufficient stem cells (33).
Additional evidence supports a role for the osteoblastic niche in supporting and maintaining HSCs. Visnjic and colleagues have demonstrated that HSCs, and, in fact, the hematopoietic system, rely on osteoblasts for support (34). This result came from studies of transgenic mice that specifically express the herpesvirus thymidine kinase (TK) gene in developing osteoblasts under the control of the collagen I promoter (Col2.3TK). The advantage of the Col2.3TK mice is the ability to inducibly ablate osteoblasts with ganciclovir (GCV), which triggers TK function. Loss of osteoblasts in GCV-treated Col2.3TK mice led to substantial decreases in the number of lymphoid, erythroid, and myeloid progenitors (including osteoclast progenitors) in the BM, followed by a decrease in the absolute number of HSCs (although the percentage of HSCs appeared only slightly changed) and reduced BM cellularity. After withdrawal of GCV, osteoblasts reappeared in the bone, as did hematopoiesis in the BM. These observations further support the role of osteoblasts in the maintenance of HSCs and regulation of hematopoiesis, although the authors did not perform functional assays to test HSCs in this model. In another study osteoblasts were shown to facilitate engraftment of HSCs in an allogeneic environment. After purified osteoblasts were cotransplanted with marrow stem cells into allogeneic mouse strains, the transplanted recipient mice demonstrated excellent long-term survival, absence of disease, and complete engraftment by the donor cells. It appeared that the HPCs could engraft lethally irradiated mice, but these cells could not cross the MHC antigen barrier in the absence of cotransplanted osteoblasts (48).