Hematopoietic stem and progenitor cells (HSPC) are essential for mature blood cell production, host immunity and osteoclast mediated bone turnover. When do stem cells give rise to all mature blood cells while maintaining their pool and how these opposite tasks are synchronized is poorly understood. Recent studies revealed that daily onset of light and darkness differentially control HSPC migration and differentiation while maintaining their bone marrow (BM) reservoir by inducing circadian bursts of BM norepinephrine (NE), TNF and melatonin. Bone forming stromal precursors are also regulated by daylight and darkness onset. These topics and their clinical potential will be discussed.
Tsvee Lapidot during his Post Doc. With John Dick developed functional preclinical models for identification and characterization of normal blood forming (Science 1992) and leukemia initiating (Nature 1994) human stem cells in transplanted immune deficient mice. Regulation of stem cell migration and development and the mechanism of clinical bone marrow transplantation are not fully understood. Over the years Tsvees laboratory at Weizmann made several key findings concerning regulation of human and murine hematopoietic stem cell homing and engraftment by the CXCR4/CXCL12 axis (Science 1999). Clinical stem cell mobilization (Nature Immunology 2002). Bone turnover and osteoclasts, (Nature Medicine 2006). The nervous system (Nature Immunology 2007). Connexin- 43 gap junction CXCL12 expression (Nature Immunology 2011). COX-2 macrophages (Nature Immunology 2012). Metabolic regulation by coagulation factors of stem cell BM retention, protection from chemotherapy, mobilization and homing by control of nitric oxide generation (Nature Medicine 2015) and stem cell ROS regulation by the blood-BM-endothelial-barrier (Nature 2016). Recently, we discovered the central role of light and darkness onset which differentially regulate following light initiation stem cell migration and development by TNF and norepinephrine and following darkness initiation stem cell maintenance and replenishment of the reservoir by melatonin and COX-2+ macrophages(Cell Stem Cell 2018).