Matrix-Embedded Osteocytes Regulate Mobilization of Hematopoietic Stem/Progenitor Cells

Abstract

The bone marrow (BM) niche comprises multiple cell types that regulate hematopoietic stem/progenitor cell (HSPC) migration out of the niche and into the circulation. Here, we demonstrate that osteocytes, the major cellular component of mature bone, are regulators of HSPC egress. Granulocyte colony-stimulating factor (G-CSF), used clinically to mobilize HSPCs, induces changes in the morphology and gene expression of the osteocytic network that precedes changes in osteoblasts. This rapid response is likely under control of the sympathetic nervous system, since osteocytes express the β2-adrenergic receptor and surgical sympathectomy prevents it. Mice with targeted ablation of osteocytes or a disrupted osteocyte network have comparable numbers of HSPCs in the BM but fail to mobilize HSPCs in response to G-CSF. Taken together, these results indicate that the BM/bone niche interface is critically controlled from inside of the bone matrix and establish an important physiological role for skeletal tissues in hematopoietic function.

Communication of bone cells with hematopoiesis, immunity and energy metabolism

“…Interestingly, exogenous osteocalcin rescued only the diabetic phenotype but not fat loss in this model. 51 Together with the fact that osteocalcin is highly expressed not only in osteoblasts but also in osteocytes, 40 and with our observations on OL mice in which glucose metabolism is not altered, but fat loss is prominent, mesenchymal lineage cells may control finely the energy metabolism depending on their differentiation stages. Moreover, osteoblasts and osteocytes may regulate preferentially glucose and fat metabolisms, respectively (Figure 4).…”

“…22 In our subsequent study, the cellular connection between endosteal osteoblasts and boneembedded osteocytes had been disrupted after G-CSF treatment. 40 However, osteolineage cells do not express G-CSF receptor. 22 As osteocytes express b2-adrenergic receptor, and surgical denervation disrupts the regulation of osteocyte specific genes, it is confirmed that osteocytes are regulated by the SNS.…”

“…In G-CSFinduced mobilization, osteoblasts are suppressed through three different pathways: (1) direct suppression by the SNS, (2) loss of supporting signals from osteomacs and (3) loss of supporting signals from osteocytes. 40 …”

Regulation of hematopoiesis in endosteal microenvironments

“…A number of important roles for osteocytes in bone biology, such as mechanosensation and mineral metabolism, have been identified in previous studies [11]. A series of recent studies, including one by our group, has revealed the importance of osteocytes in the regulation of hematopoiesis [12][13][14]. In this review, we provide an overview of advances in our knowledge of regulatory mechanisms in the hematopoietic system by osteolineage cells in the endosteal area.…”

“…G-CSF increases sympathetic tone and eliminates endosteal macrophages, which also causes alteration of the HSC/HPC niches. In a recent study, our group assessed osteocyte function in regulating HSC/ HPC mobilization induced by G-CSF [13]. Analysis of gene expression profile of osteoblasts and osteocytes in mice during G-CSF treatment revealed that osteocytes are suppressed by G-CSF treatment in the same manner as osteoblasts.…”