Emergency granulopoiesis is a critical process by which hematopoietic progenitors and stem cells facilitate enhanced granulocytic production during severe infections. However, the role of distinct multipotent progenitors (MPPs) at early stages of this process remains underexplored. Here, we investigated the contribution of MPPs to granulocytic production following lipopolysaccharide (LPS) administration in wild-type mice, simulating a bacterial infection. Transplantation assays demonstrated that LPS exposure reduces the engraftment capacity of lymphoid-biased MPP4 and enhances lymphoid production, rather than supporting myeloid lineage output. Further, single-cell RNA sequencing (scRNA-seq) of MPPs isolated from control and LPS-challenged mice revealed transcriptional reprogramming of nonlineage committed MPPs toward myeloid- and erythroid-biased progenitors. Notably, inflammatory progenitor populations emerged on activation of LPS-induced emergency granulopoiesis, displaying chromatin accessibility changes that align with a commitment to myeloid and erythroid fates. Pseudotime analysis elucidated cellular trajectories that suggest a developmental pathway where unbiased progenitors, present under nonstress conditions, transition toward myeloid and erythroid lineage outputs on LPS administration. In line with our functional MPP4 assessment, scRNA-seq suggested that lymphoid-biased progenitors do not transcriptionally rewire during early stages of emergency granulopoiesis. Collectively, our data highlight the critical role of specific MPP subsets in responding to LPS-induced inflammatory signals and underscore the dynamic adaptations that occur during granulocyte production in response to infection.

Childhood Leukaemia Investigation Prague Department of Pediatric Haematology and Oncology 2 Faculty of Medicine Charles University Prague University Hospital Motol Prague Czech Republic

Faculty of Science Charles University Prague Czech Republic

Institute of Biotechnology of the Czech Academy of Sciences Prague West Czech Republic

Laboratory of Bioinformatics and Computational Genomics Faculty of Mathematics and Information Science Warsaw University of Technology Warsaw Poland

Laboratory of Functional and Structural Genomics Centre of New Technologies University of Warsaw Warsaw Poland

Laboratory of Hemato oncology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Section for Computational and RNA Biology Department of Biology University of Copenhagen Copenhagen Denmark

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