Monocytic Cells Mediate Granulocyte-Colony Stimulating Factor-Induced Mobilization of Hematopoietic Stem and Progenitor Cells

In the normal, healthy adult, hematopoiesis occurs primarily in the bone marrow. As such, at steady state, a majority of hematopoietic stem and progenitor cells: HSPCs) are tightly held within specialized areas of the bone marrow collectively referred to as the `hematopoietic stem cell niche.\u27 In response to various forms of stress, such as infection or hemorrhage, or following administration of a variety of pharmacologic agents, niche function is altered and HSPCs are released into the peripheral circulation through a process known as mobilization. Granulocyte-colony stimulating factor: G-CSF), a hematopoietic growth factor, is the most widely-used mobilizing agent clinically. However, the mechanisms by which G-CSF elicits HSPC mobilization are not well-understood. The experiments described herein are directed towards understanding the mechanism by which G-CSF elicits mobilization as a means to understanding regulation of HSPC trafficking between the bone marrow and periphery. We first focused on identifying the hematopoietic lineage directly targeted by G-CSF in the initiation of HSPC mobilization. Using a mouse model in which the G-CSF receptor is selectively expressed on monocytic cells, we demonstrate that G-CSF signaling in monocytic cells is sufficient for a normal mobilization response. Subsequent studies were designed to identify which of the three major cell types within the monocytic lineage - bone marrow macrophages, osteoclasts, and myeloid dendritic cells - are critical for retention of HSPCs within the bone marrow and for the mobilization response to G-CSF. We demonstrate that loss of myeloid dendritic cells does not abrogate the mobilization response to G-CSF and that pharmacologic ablation of osteoclasts does not lead to HSPC release into the periphery. Lastly, we evaluated the importance of selected factors produced by monocytes in the mobilization response to G-CSF. We demonstrate that hematopoietic loss of osteopontin does not alter the mobilization response to G-CSF. Further work will be required to evaluate the role of bone marrow macrophages and myeloid dendritic cells in HSPC retention as well as the requirement for osteoclasts in G-CSF-induced mobilization. Future studies will be directed at identifying the factors used by monocytic cells to communicate with the stromal components of the HSPC niche during G-CSF-induced mobilization

Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice

Expression of the G-CSF receptor on bone marrow monocytes is sufficient to trigger HSC mobilization in response to G-CSF, in part via effects on osteoblast lineage cells

How to do it: the difficult thyroid

There is a paucity of publications detailing how to deal with the difficult thyroid cancer. When compared to other cancers, it is relatively rare with several histopathological subtypes which run differing clinical courses and respond to different therapies. It is a condition predominately treated by specifically trained General and now ENT surgeons who already have a thorough knowledge of vocal fold assessment and rehabilitation as well as emergency airways management both to avoid and treat common complications should they occur