CHRONIC LUNG INFLAMMATION LEADS TO MYELOID SKEWING OF HEMATOPOIETIC STEM CELLS IN A CYSTIC FIBROSIS MOUSE MODEL

Persistent lung inflammation is a hallmark of Cystic fibrosis (CF) lung disease. Inflammation can lead to functional decline in hematopoietic stem cell (HSCs), tipping the balance towards myelopoiesis and contributing to chronic inflammation. However, it’s unknown whether the HSCs are dysfunctional in CF. We tested whether chronic lung inflammation impacts hematopoietic stem and progenitor cells (HSPCs) in a CF mouse model.

Wild-type (WT) and Cftr -/- mice were nebulized with lipopolysaccharide (LPS) from Pseudomonas aeruginosa for 5 weeks. The mice were euthanized before the exposure (T0), 24 hours after the last LPS nebulization (T1), or 6 weeks (T2) after the last LPS nebulization. The bone marrow (BM) and lung tissue were collected for flow cytometry analysis of the HSPC population and immune cells in the lungs, respectively. Peripheral blood was collected for complete blood count analysis.

At baseline, Cftr -/- mice show a larger HSPC population with a myeloid bias, indicated by higher frequencies of LSK, LT-HSC, CD41 ⁺ LT-HSC, GMPs, and MkPs. Following chronic LPS nebulization, Cftr -/- mice exhibit greater HSPC expansion and myeloid differentiation, alongside increased peripheral myeloid cell counts. Post-recovery, while most HSPC populations return to baseline, Cftr -/- mice retain elevated myeloid-biased LT-HSCs, suggesting a persistent myeloid bias. These findings underscore a prominent shift toward myeloid hematopoiesis in CF, which is accentuated by chronic inflammation and remains even after recovery.

Further experiments are underway to assess maladaptive epigenetic changes in HSC as well as if chronic lung inflammation impacts HSC functionality.