Daily light and darkness onset and circadian rhythms metabolically synchronize hematopoietic stem cell differentiation and maintenance: The role of bone marrow norepinephrine, tumor necrosis factor, and melatonin cycles.

Hematopoietic stem and progenitor cells (HSPCs) are essential for daily mature blood cell production, host immunity, and osteoclast-mediated bone turnover. The timing at which stem cells give rise to mature blood and immune cells while maintaining the bone marrow (BM) reservoir of undifferentiated HSPCs and how these opposite tasks are synchronized are poorly understood. Previous studies revealed that daily light onset activates norepinephrine (NE)-induced BM CXCL12 downregulation, followed by CXCR4⁺ HSPC release to the circulation. Recently, we reported that daily light onset induces transient elevations of BM NE and tumor necrosis factor (TNF), which metabolically program BM HSPC differentiation and recruitment to replenish the blood. In contrast, darkness onset induces lower elevations of BM NE and TNF, activating melatonin production, which metabolically reprograms HSPCs, increasing their short- and long-term repopulation potential, and BM maintenance. How the functions of BM-retained HSPCs are influenced by daily light and darkness cycles and their clinical potential are further discussed.