Mechanisms of TLR4-mediated impairment of murine and human HSCs (HEM2P.258)

Chronic exposure to toll-like receptor 4 (TLR4) ligand drives murine hematopoietic stem cell (HSC) exhaustion and loss of lymphoid potential. This finding is significant because TLR4 is activated by plasma lipopolysaccharide (LPS) that is elevated in patients with chronic infection as well in obese individuals. For the first time, we show that human HSCs are severely compromised by TLR4 stimulation. Mice engrafted with human cord blood cells and then exposed to low-dose LPS have variably reduced human CD34+ HSCs with near complete ablation of downstream common lymphoid progenitor (CLP) and B cell precursor subsets in bone marrow. By contrast, myeloid precursors are grossly intact. Peripheral tissue subsets similarly exhibit myeloid>lymphoid skewing. We have shown that LPS-exhausted murine HSCs have reduced levels of the major transcription factor E47. Our newly published findings demonstrate a mechanistic link between E47 and the p21 cell cycle regulator. CD150+ HSCs from mice doubly haploinsufficient for E47 and p21 exhibit hyperproliferation, poor self-renewal, and selective myeloid bias. Finally, we show that murine CD150+ HSC and multipotent progenitors (MPP) express TLR4, and directly respond to LPS in a TLR4-dependent manner. Together, our findings suggest that chronic activation of TLR4 damages the functional integrity of not only murine HSC but also human HSC in vivo, via a mechanism linked to disruption of the E47-p21 pathway.