Rapid Response of Neutrophils Determined by Shortest Differentiation Trajectory and New Insight into Cell Cycle Kinetics and Chronological Order of Progenitor States

Despite substantial advances in our understanding of hematopoietic stem cell self-renewal, differentiation, and proliferation, the underlying mechanisms and cell cycle kinetics remain elusive. Neutrophils, as primary rapid responders during infections, quickly generate an enormous number of mature cells for immune defense. This immune phenomena is effected by cell cycle kinetics. Our previous study redefined progenitors and reformed the hierarchy of hematopoiesis. How exactly lineage commitment and cell cycle are coordinated remain to be elucidated. Here, we aim to elucidate the cell cycle kinetics and chronological order of progenitor states, providing new insights into immune phenomena. We revealed the changes in cell cycle kinetics from differentiation (lineage commitment) to proliferation (cell division) in peripheral hematopoiesis. Differentiating hematopoietic progenitor cells (HPCs) are maintained in the G1 phase of cell cycle, regulated by DNA replication. CDCA7 was identified as an essential factor for DNA replication, facilitating the transition of progenitor cells from G1 to S phase. Once the progenitors complete their commitment, cell cycle states of progenitors convert from G1 to S phase, switching from lineage commitment to cell division with DNA replication begins. Lineage commitment and cell division of MPCs are independent processes, and fate determination takes precedence over proliferation. Since the differentiating HPCs do not undergo cell division, a committing progenitor will destined to mature into only one committed progenitor cell along its designated differentiation trajectory. The chronological order of quiescence, self-renewal, differentiation, and proliferation, was clearly delineated. Our study proposed the concept of " temporal sequence control ," emphasizing that fate determination necessarily precedes division during lineage commitment, thereby providing a new dimension for modeling hematopoietic dynamics. Our study reveals that initial progenitors in adult peripheral blood exhibit self-renewal capabilities, which are absent after lineage commitment is completed during hematopoiesis. Neutrophil present the shortest differentiation trajectory in the hematopoietic hierarchy, which decide their role as rapid responders. Our results provide a clear characterization of the cell cycle kinetics of HPCs’ lineage commitment and cell division, facilitating advancements in inflammation and disease treatment.