Kosanovic Sladjana, Vanickova Karolina, Milosevic Mirko, Ribeiro Bas Irina, Chilinski Mateusz, Plewczynski Dariusz, Danek Petr, Rohlena Jakub, Rohlenova Katerina, Alberich-Jorda Meritxell
Laboratory of Hemato-oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic; Faculty of Science, Charles University, Prague, Czech Republic.
Institute of Biotechnology of the Czech Academy of Sciences, Prague-West, Czech Republic.
Exp Hematol. 2025 Jul;147:104792. doi: 10.1016/j.exphem.2025.104792. Epub 2025 Apr 30.
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.
应急粒细胞生成是一个关键过程，通过该过程造血祖细胞和干细胞在严重感染期间促进粒细胞生成增强。然而，在此过程早期不同多能祖细胞（MPP）的作用仍未得到充分探索。在这里，我们研究了MPP在野生型小鼠给予脂多糖（LPS）后对粒细胞生成的贡献，模拟细菌感染。移植试验表明，LPS暴露降低了偏向淋巴细胞的MPP4的植入能力，并增强了淋巴细胞生成，而不是支持髓系谱系输出。此外，对从对照小鼠和LPS刺激小鼠中分离出的MPP进行单细胞RNA测序（scRNA-seq），揭示了未分化的MPP向偏向髓系和红系祖细胞的转录重编程。值得注意的是，炎症祖细胞群体在LPS诱导的应急粒细胞生成激活时出现，显示出与向髓系和红系命运分化一致的染色质可及性变化。伪时间分析阐明了细胞轨迹，表明存在一条发育途径，即在非应激条件下存在的未偏向祖细胞在给予LPS后向髓系和红系谱系输出转变。与我们对MPP4的功能评估一致，scRNA-seq表明偏向淋巴细胞的祖细胞在应急粒细胞生成早期不会发生转录重排。总的来说，我们的数据突出了特定MPP亚群在响应LPS诱导的炎症信号中的关键作用，并强调了在粒细胞生成过程中响应感染时发生的动态适应性变化。
