Systematic dissection of coordinated stromal remodeling identifies Sox10+ glial cells as a therapeutic target in myelofibrosis

Remodeling of the tissue niche is often evident in diseases, yet, the stromal alterations and their contribu-tion to pathogenesis are poorly characterized. Bone marrow fibrosis is a maladaptive feature of primary myelofibrosis (PMF). We performed lineage tracing and found that most collagen-expressing myofibro-blasts were derived from leptin-receptor-positive (LepR+) mesenchymal cells, whereas a minority were from Gli1-lineage cells. Deletion of Gli1 did not impact PMF. Unbiased single-cell RNA sequencing (scRNA-seq) confirmed that virtually all myofibroblasts originated from LepR-lineage cells, with reduced expression of hematopoietic niche factors and increased expression of fibrogenic factors. Concurrently, endothelial cells upregulated arteriolar-signature genes. Pericytes and Sox10+ glial cells expanded drasti-cally with heightened cell-cell signaling, suggesting important functional roles in PMF. Chemical or genetic ablation of bone marrow glial cells ameliorated fibrosis and improved other pathology in PMF. Thus, PMF involves complex remodeling of the bone marrow microenvironment, and glial cells represent a promising therapeutic target.

Automated summary

Remodeling of the bone marrow microenvironment is observed in primary myelofibrosis (PMF), characterized by expansion of collagen-expressing myofibroblasts derived from LepR+ mesenchymal cells and upregulation of arteriolar-signature genes in endothelial cells. Unbiased single-cell RNA sequencing confirmed the origin of myofibroblasts and revealed reduced expression of hematopoietic niche factors and increased expression of fibrogenic factors. Expansion of pericytes and Sox10+ glial cells and enhanced cell-cell signaling suggest their functional roles in PMF. Targeting bone marrow glial cells could ameliorate fibrosis and improve pathology in PMF.