Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.04.23.590178

Rapid Response of Neutrophils Determined by Shortest Differentiation Trajectories and Absence of Self-Renewal in committed Progenitors

Yue, Y.
View original source ↗Export metadata ↓

Abstract

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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/590178v3_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@12f9c62org.highwire.dtl.DTLVardef@c3fe21org.highwire.dtl.DTLVardef@1615922org.highwire.dtl.DTLVardef@22d225_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Lineage commitment progresses independently of cell division, where each progenitor differentiates into a single terminally committed cell (Panel B), challenging the conventional paradigm that cell division occurs at each step of lineage commitment (A).s C_FIG

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Yue, Y.. 2024-04-27. Rapid Response of Neutrophils Determined by Shortest Differentiation Trajectories and Absence of Self-Renewal in committed Progenitors. https://doi.org/10.1101/2024.04.23.590178

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Functional characterization of Rho GTPase activating proteins SYDE1 and SYDE2

The human genome encodes more than 60 proteins containing Rho GTPase activating protein (RhoGAP) domains, many of which remain understudied with respect to their target specificity and biological roles. SYDE1 and SYDE2 are two such orphan RhoGAPs, for which there are few studies characterizing their biochemical and cellular functions and conflicting reports identifying their cognate GTPases. We previously identified SYDE1 and SYDE2 in a screen for substrates of the c-Jun N-terminal kinases. Here, we show that SYDE1 and SYDE2 are preferentially phosphorylated by JNK1 relative to other mitogen-activated protein kinases (MAPKs) at sites proximal to a kinase docking region. Purified SYDE1 and SYDE2 are shown to have significant catalytic GAP activity toward RhoA, Rac1, and Cdc42. However, neither up- nor down-regulation of SYDE1/2 expression leads to detectable changes in bulk GTP loading of any of these GTPases. Nevertheless, we demonstrate that SYDE1 and SYDE2, in a partially GAP-dependent manner, increase cell spreading and number of focal adhesions, and promote more directionally persistent migration in HEK293 cells. Together, these findings establish SYDE1 and SYDE2 as robust JNK substrates with catalytic activity toward a set of Rho GTPases and reveal basic functions of SYDE1 and SYDE2 in regulating cell morphology, adhesion, and migration.

cell biology↗
bioRxiv2026

The filopodial scaffold polyphosphate dictates cell adhesion-versus-invasion decisions

Inorganic polyphosphate (polyP) is an ancient polymer conserved across all life, serving cell type and location specific functions in every major compartment. Yet its role at the plasma membrane, where it accumulates to peak levels in many primary cells, is largely unknown. Here we identify polyP as a stabilizing component of filopodia, actin based membrane protrusions that govern cell adhesion, contact inhibition, and chemotaxis. Elevating cellular polyP increases filopodial stability and enhances cell adhesion, whereas reducing polyP accelerates filopodial disassembly and promotes cell migration. Mechanistically, we find that polyP acts as a structural filopodial scaffold, recruiting and organizing IRSp53, a membrane curvature inducing protein. We show that metastatic fibroblasts and breast cancer organoids carry markedly reduced and intracellularly reorganized polyP levels relative to their non transformed counterparts. Restoring endogenous polyP via lipid nanoparticle delivery suppresses their invasive phenotypes and reverses prometastatic gene expression signatures, implicating polyP as a primordial tumor suppressor.

cell biology↗
bioRxiv2026

Mitochondrial transfer mediates metabolic communication between beta cells and islet macrophages

Pancreatic islet macrophages support islet homeostasis and adapt their metabolic program in response to environmental cues, including beta cell released factors. Intercellular mitochondrial transfer is a biological process that modulates cellular responses. To test whether beta cells, which are strongly secretory, transfer mitochondria to islet macrophages, we generated mice with beta cell-specific expression of mitochondrial GFP (PhAMfloxIns1Cre). We demonstrate that beta cells transfer mitochondria to islet macrophages in vivo and in vitro. Diabetogenic stressors did not alter the frequency of mitochondrial transfer and macrophages containing beta cell-derived GFP exhibit increased protein synthesis rates. RNA-seq identified upregulation of activity-regulated cytoskeleton associated protein (Arc) in macrophages receiving beta cell-derived mitochondria, while disruption of actin cytoskeleton dynamics prevented mitochondrial transfer. Together, these findings identify mitochondrial transfer as a previously unrecognized mechanism of beta cell-macrophage communication that may contribute to islet homeostasis and immune regulation.

cell biology↗