Spatiotemporal mapping of human myelofibrosis reveals druggable principles of fibrosis progression and reversal

Fibrosis is a final common pathway of organ failure, yet, whether it can be reversed remains unresolved. Myelofibrosis (MF) in myeloproliferative neoplasms (MPNs) regresses after allogeneic stem cell transplantation (allo-HSCT), offering a unique clinical paradigm. We generated a single-cell map of immune and stromal populations from 19 control and patient-derived MF bone marrow biopsies before and after allo-HSCT. Adipogenic CXCL12-abundant reticular (Adipo-CAR) cells emerged as the fibrosis-driving stromal subset. Interferon response programs dominated the fibrotic niche and SPP1+ macrophages formed a central cellular communication hub. Integrating single-cell and spatial proteomics revealed TGF-β–driven crosstalk between megakaryocytes and Adipo-CARs that rewired after allo-HSCT, preceding histological regression of fibrosis, representing a therapeutic window of opportunity. Single-cell genotyping mapped mutant hematopoietic clones and identified CD93 as a clinically relevant mediator of niche interactions. Residual mutant macrophages persisted post-allo-HSCT in a transcriptionally altered state. PDE5A expression in Adipo-CARs tracked fibrosis progression and reversal. Its genetic and pharmacologic targeting reduced fibrosis in vitro and in vivo. These findings establish a cellular and molecular framework for fibrosis reversal in humans, reveal how the bone marrow niche normalizes from fibrosis ahead of histological recovery, and open avenues for disease-modifying therapies beyond transplantation.

• Type: RNASeq
• Archive: European Genome-phenome Archive (EGA)