Clonal Hematopoiesis Drives Fibrotic Remodeling of the Bone Marrow Microenvironment [dataset 3]

ABSTRACT: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with systemic inflammation and increased malignant risk, yet how it reshapes the bone marrow (BM) niche remains poorly understood. Using single-cell transcriptomic profiling of freshly isolated BM, we identify fibro-inflammatory remodeling as an early hallmark of CHIP. Beyond the established myeloid-biased inflammatory state, CHIP BM displayed coordinated TNFα activation spanning hematopoietic progenitors, monocytes, and stromal cells. Stromal populations showed early fibrotic remodeling, with mesenchymal and vascular cells upregulating collagen and extracellular matrix gene programs. Fibroblasts were markedly expanded regardless of mutational subtype and acquired cancer-associated fibroblast (CAF)-like transcriptional states. Histological analysis confirmed the presence of pre-fibrotic stromal remodeling in CHIP BM, representing an early and potentially disease-defining pathological change. Spatial transcriptomics further revealed discrete fiber-enriched regions populated by active and CXCL12⁺ fibroblasts, macrophages, and lymphoid cells, establishing fibroblast-immune crosstalk as a defining architectural feature of the CHIP niche. Strikingly, these regions were characterized by significant enrichment of pro-inflammatory pathways, including TGF-β and TNF signaling, identifying them as spatially confined inflammatory hubs within the BM microenvironment. Together, these findings establish fibro-inflammatory BM remodeling as a conserved early consequence of clonal expansion, linking CHIP to prefibrotic stromal changes, immune dysregulation, and a niche architecture that may prime the transition to overt malignancy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336159 | GEO | 2026/08/13

REPOSITORIES: GEO