Chronic lung inflammation disrupts the quiescent state of hematopoietic stem cells in a cystic fibrosis mouse model

---

Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B877
Abstract ID: 6002

Presenting Author:
Cassia L Braga , Postdoctoral associate at Yale Sch. of Med.

Abstract:

Persistent neutrophilic lung inflammation is a hallmark of Cystic fibrosis (CF) lung disease. Since inflammation affects hematopoietic stem cell (HSCs) proliferation and differentiation toward the myeloid lineage, here we tested the hypothesis that chronic lung inflammation in CF causes expansion of HSCs with a pathological skewing toward myelopoiesis. WT and CF-KO mice were nebulized with LPS for 5 weeks. At 24 hours (T1) or 6 weeks (T2) after the last LPS nebulization mice were euthanized. At T0, T1, and T2 the bone marrow (BM) was collected. Lineage-negative BM cells were obtained and the percent (%) of HSC, multipotent progenitors committed to myelopoiesis (MPP2, MPP3), and lymphopoiesis (MPP4) were assessed. RNA and ATAC sequencing analyses were performed in HSC. At T1, HSC and myeloid-biased multipotent progenitors (MPP2, MPP3) % were higher in CF than in WT. At T2, the % of HSC remained elevated in CF. At T2 CF HSCs retain several increased chromatin-accessible regions and differentially expressed genes (DEGs), while WT HSCs return to their baseline.  Biological analysis of DEGs and open chromatin regions in CF HSC at T2 showed pathways associated with proliferation and skew toward myelopoiesis as well as a pro-inflammatory signature. Altogether, our data show that chronic lung inflammation has a long-lasting impact on CF HSCs. Future studies aim to assess the impact of HSC dysregulation on the progression of CF lung diseases and the response to airway infections.