CCL5 exposure promotes acute and transient megakaryopoiesis and hematopoietic progenitor expansion

During inflammation, megakaryocytes (MKs) can expand from hematopoietic stem cells, yet the specific driving factors remain unclear. We investigated whether C-C Motif Chemokine Ligand 5 (CCL5) influences this process in murine and human iPSC-derived bone marrow organoid (BMO) models. Acute CCL5 administration to mice increased hematopoietic stem and progenitor cell (HSPC) populations and increased MKs, including the expansion of MHC II-expressing MKs, characteristic of the immune MK subpopulation. Mechanistically, MK progenitors upregulated CCR1 and CCR5, and MKs showed increased phosphorylation of JAK1, SRC, and STAT1-5. Phenotypically, transcriptomic profiling revealed enhanced expression of genes associated with the cell cycle, inflammatory pathways, and mitochondrial metabolism in MKs isolated from CCL5-treated mice, which was functionally supported by increased mitochondrial activity. Similarly, in human BMOs, CCL5 treatment increased MK numbers. Together, these findings implicate CCL5 as a direct mediator of acute megakaryopoiesis and immune MK expansion during inflammation.