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

Abstract

AbstractDespite 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. 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 in peripheral hematopoiesis. Differentiating hematopoietic progenitor cells (HPCs) are maintained in the G1 phase of cell cycle, regulated by DNA replication. Once the progenitors complete their commitment, cell cycle states of progenitors convert from G1 to S phase, switching from differentiation to proliferation with DNA replication begins. Differentiation and proliferation 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 on its selected differentiation path. The chronological order of quiescence, self-renewal, differentiation, and proliferation, is clearly delineated. Our study reveals that initial progenitors in adult peripheral blood exhibit self-renewal capabilities, which are absent after lineage commitment is completed during hematopoiesis. Furthermore,GATA2andCSF3Rwere confirmed as key transcription factors determining the co-segregation among neutrophils and other lineages, deciphering the underlying molecular mechanisms. 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’ differentiation and proliferation, facilitating advancements in inflammation and disease treatment.