Authors:
Shane R Mayack and Amy J Wagers
Summary:
Recent studies using gene-targeted and hormone-treated mice have implicated bone-lining osteoblasts as important regulators of hematopoietic stem cell (HSC) self-renewal and differentiation; however, as much of the evidence supporting this notion derives from indirect in vivo experiments, which are unavoidably complicated by the presence of other cell types within the complex bone marrow milieu, the sufficiency of osteoblasts in modulating HSC activity has remained controversial 1. To address this issue, we prospectively isolated mouse osteoblasts, using a novel, flow cytometry-based approach, and directly tested their activity as HSC niche cells and their role in cyclophosphamide/G-CSF (Cy/G) induced HSC proliferation and mobilization. We found that osteoblasts expand rapidly following Cy/G treatment and exhibit significant phenotypic and functional changes that directly influence their ability to support HSC proliferation and maintenance of reconstituting potential. Furthermore, these effects of mobilization on osteoblast number and function depend on the function of ATM, the product of the ataxia telangiectasia mutated (Atm) gene, demonstrating a new role for this kinase in supporting stem cell niche activity. Taken together, these studies demonstrate that signals from osteoblasts can directly initiate and modulate HSC proliferation in the context of mobilization. More broadly, this work establishes that direct interaction with the osteolineage niche cell itself - in the absence of additional environmental inputs - is sufficient to modulate stem cell activity.
Source:
Blood; (05/02/08)