Dissecting the Functional Reprogramming of the Microenvironment in Bone Marrow Fibrosis at the Single Cell Level

Functional contributions of individual members of the bone marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPN) are incompletely understood. Consequently, we aimed to generate a comprehensive map of the stroma in MPN/MF on a single cell level. Our analysis revealed two distinct mesenchymal stromal cells (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-fibrotic stage and acquisition of a pro-fibrotic and inflammatory phenotype in the fibrotic stage. In parallel, IL-33-expressing myelinating Schwann cell progenitors expanded, likely as a repair mechanism for the previously described neuropathy in MPN. IL-33 had anti-fibrotic effects on MSCs but induced expression of the alarmin S100A8 leading to loss-of-hematopoiesis support. Importantly, we demonstrate that S100A8 expression in stroma and patient plasma marks fibrosis progression and might even serve as a biomarker for disease progression.