Role of osteoclasts in regulating hematopoietic stem and progenitor cells

Abstract

Bone marrow (BM) cavities are utilized for hematopoiesis and to maintain hematopoietic stem cells (HSCs). HSCs have the ability to self-renew as well as to differentiate into multiple different hematopoietic lineage cells. HSCs produce their daughter cells throughout the lifespan of individuals and thus, maintaining HSCs is crucial for individual life. BM cavities provide a specialized microenvironment termed "niche" to support HSCs. Niches are composed of various types of cells such as osteoblasts, endothelial cells and reticular cells. Osteoclasts are unique cells which resorb bones and are required for BM cavity formation. Loss of osteoclast function or differentiation results in inhibition of BM cavity formation, an osteopetrotic phenotype. Osteoclasts are also reportedly required for hematopoietic stem and progenitor cell (HSPC) mobilization to the periphery from BM cavities. Thus, lack of osteoclasts likely results in inhibition of HSC maintenance and HSPC mobilization. However, we found that osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization by using three independent osteoclast-less animal models. In this review, I will discuss the roles of osteoclasts in hematopoietic stem cell maintenance and mobilization.

Human Cytomegalovirus Latency and Reactivation in and Beyond the Myeloid Lineage

“…It is possible that an initial primary infection is set up in an extremely long-lived pluripotent hematopoeitic progenitor. While such very long-lived progenitor populations are believed to exist in vivo [42], it seems unlikely that a single initial infection provides sufficient latently infected hematopoietic progenitors for the lifetime of the host. We favor the view that, in normal healthy HCMV seropositive carriers, subclinical reactivation routinely occurs during persistent carriage and these, or multiple subclinical reinfections, continually reseed new hematopoietic progenitors during the life of the host.…”

“…Nevertheless, we cannot formally rule out that a self-renewing hematopoetic progenitor population maintains a latently replicating form of the viral genome. Although there is no direct evidence for such a mechanism of latent viral genome maintenance, a recent analysis of transcripts during natural HCMV latency detected transcripts associated with viral DNA replication and proteins encoded by these RNAs could associate with viral genomes from experimentally latently infected cells [42]. Attractively, in these studies, the terminal repeat region of the viral genome appeared to provide a cis-acting genome maintenance function [40].…”

The “soft” side of the bone: unveiling its endocrine functions

“…Finally, the role of osteoclasts in the regulation of hematopoietic stem cells (HSCs) by degrading endosteal components, which in turn leads to mobilization of hematopoietic progenitors, has been recently discovered [15]. A correlation between osteoclasts and HSCs is also supported by evidence that treatment with anti-resorptive agents such as bisphopshonates and anti-RANKL antibodies, which reduce the number of osteoclasts, increases the number of HSCs mobilized from the bone marrow [16].…”

Reprint of: The Great Beauty of the osteoclast

“…Furthermore, impairment of osteoclast function by bisphosphonates reduces HSC number in bone marrow [95] and abolishes the HSC increment induced by PTH. Granulocyte-colony stimulating factor (G-CSF) administration increases bone resorption concomitant to the egress of HSCs, and antiosteoclastic agents, such as bisphosphonates or anti-RANKL antibody, increase the number of HSC mobilized from bone marrow [96][97][98]. The number of HSCs mobilized into the blood is higher in mice with osteopetrotic genotypes, including the M-CSF, the RANKL-and the c-Fos-deficient mice, and lower in mice lacking the anti-osteoclastogenic cytokine, OPG [98].…”

“…Granulocyte-colony stimulating factor (G-CSF) administration increases bone resorption concomitant to the egress of HSCs, and antiosteoclastic agents, such as bisphosphonates or anti-RANKL antibody, increase the number of HSC mobilized from bone marrow [96][97][98]. The number of HSCs mobilized into the blood is higher in mice with osteopetrotic genotypes, including the M-CSF, the RANKL-and the c-Fos-deficient mice, and lower in mice lacking the anti-osteoclastogenic cytokine, OPG [98]. These observations suggest a complex role for osteoclasts in the control of HSC maintenance and mobilization, although the information is still fragmented and incomplete, requiring more work for a full elucidation of the underlying mechanisms.…”