Adiponectin receptors sustain hematopoietic stem cells throughout adulthood by protecting them from inflammation

How are hematopoietic stem cells (HSCs) protected from inflammation, which increases with age and can deplete HSCs? Adiponectin, an anti-inflammatory factor that is not required for HSC function or hematopoiesis, promotes stem/progenitor cell proliferation after bacterial infection and myeloablation. Adiponectin binds two receptors, AdipoR1 and AdipoR2, which have ceramidase activity that increases upon adiponectin binding. We found adiponectin receptors are non-cell-autonomously required in hematopoietic cells to promote HSC quiescence and self-renewal. Adiponectin receptor signaling suppresses inflammatory cytokine expression by myeloid cells and T cells, including interferon gamma (IFNγ) and tumor necrosis factor (TNF). Without adiponectin receptors, the levels of these factors increase, chronically activating HSCs, reducing their self-renewal potential, and depleting them during aging. Pathogen infection accelerates this loss of HSC self-renewal potential. Blocking IFNγ or TNF signaling partially rescues these effects. Adiponectin receptors are thus required in immune cells to sustain HSC quiescence and to prevent premature HSC depletion by reducing inflammation.