Stress-Induced Activation of Dormant Hematopoietic Stem Cells In Vivo,

Abstract 3390

Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs), which are characterized by pluripotency and life long self-renewal capacity. In order to both maintain a supply of mature blood cells and not exhaust HSCs throughout the lifespan of the organism, most adult HSCs remain quiescent and only a limited number are cycling at any given time. The balance between self-renewal and differentiation of HSCs is controlled by external factors such as chemokines, as well as interactions of HSCs with its niche environment.

We have recently shown that the cytokine IFNa very efficiently activates dormant HSCs in vivo. Within hours after treatment of mice with IFNa HSCs exit G₀ and enter the active cell cycle. In general, IFNa is produced in response to viral infections by cells of the immune system, and plays an important role in the host defense against the viral infection. We now questioned whether endogenous IFNa is also produced in response to other forms of bone marrow stress and whether this affects the proliferation rate of HSCs. To monitor IFNa production in the bone marrow in vivo, we have generated MxCre; ROSA-R26-EYFP mice and found that treatment with both the chemotherapeutic agent 5-FU as well as the endotoxin LPS leads to the production of IFNa in HSCs and progenitors. In addition, LPS treatment in vivo induced a strong increase in proliferation of HSCs. In contrast to the direct effect of IFNa on HSCs, in vivo and in vitro experiments have shown that the LPS induced activation of HSCs is triggered via an indirect effect of LPS on CD11b+ cells in the bone marrow. Activation of these cells via TLR4 signaling then results in increased proliferation of the HSCs, a mechanism we are currently investigating in more detail.

Interestingly, LPS induced activation correlated with increased expression of Sca-1 on HSCs, similar to the increased Sca-1 expression upon IFNa treatment. As for IFNa, the upregulation of Sca-1 is required for LPS induced proliferation, since Sca-1^−/− mice do not respond to LPS stimulation. Furthermore, cDNA array comparisons between HSCs treated with IFNa or LPS suggest a more common mechanism of activation, independent of the source leading to the activation.

In summary, these data suggest that in addition to viral infection also other forms of bone marrow stress, like LPS, result in activation of quiescent HSCs in the bone marrow, probably via similar mechanisms. Furthermore, both IFNa and LPS induced activation of HSCs are dependent on the up-regulation of Sca-1, suggesting a more general role for Sca-1 in the activation of stem cells.