NicheSphere reveals an Spp1-centered multicellular niche in myeloproliferative neoplasm-associated fibrosis

ABSTRACT: Bone marrow fibrosis in myeloproliferative neoplasms arises through reciprocal interactions between mutant hematopoietic cells and fibrosis-associated stromal populations. Using dual lineage tracing, single-cell and multiplet RNA sequencing, spatial proteomics, and NicheSphere, a framework integrating condition-specific co-localization with ligand–receptor inference, we identified an Spp1-centered multicellular ‘Fibrosis interacting core’ comprising osteoCAR cells, fibroblasts, megakaryocytes and additional hematopoietic populations, in which Spp1⁺ myeloid cells occupied a central communication position. NicheSphere distinguished macrophage–vascular compartments enriched in inflammatory signaling from this “Fibrosis interacting core” characterized by TGF-β, NF-κB, and extracellular-matrix programs. CODEX imaging confirmed increased proximity of SPP1⁺ immune cells, activated stromal cells, and megakaryocytes. Genetic deletion of Spp1 demonstrated complementary functional contributions from stromal and hematopoietic compartments, supporting Spp1 as a multicellular mediator of fibrosis, inflammation and myeloproliferative features rather than a macrophage-restricted effector.. Human myelofibrosis single-cell analysis identified SPP1⁺ cells as a prominent predicted communication hub, while elevated circulating SPP1 was associated with adverse clinical outcome. Together, these findings define SPP1-centered multicellular communication as a conserved feature of the fibrotic niche and identify SPP1-associated signaling as a potential therapeutic vulnerability in myelofibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE347294 | GEO | 2026/09/15

REPOSITORIES: GEO