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

• Published in: Cell stem cell 2023-06, Vol.30 (6), p.832-850.e6
• Main Authors: Sarkaria, Shawn M., Zhou, Junsong, Bao, Suying, Zhao, Wenqi, Fang, Yinshan, Que, Jianwen, Bhagat, Govind, Zhang, Chaolin, Ding, Lei
• Format: Article
• Language: English
• Subjects: Bone Marrow - metabolism; Endothelial Cells - metabolism; Gli1; glial cells; hematopoietic stem cells; Humans; LepR; lineage tracing; mesenchymal stromal cells; microenvironmental niche; myelofibrosis; Neuroglia - metabolism; Primary Myelofibrosis - drug therapy; single-cell RNA sequencing; SOXE Transcription Factors - genetics; SOXE Transcription Factors - metabolism; Zinc Finger Protein GLI1 - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2023.05.002

Remodeling of the tissue niche is often evident in diseases, yet, the stromal alterations and their contribution 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 myofibroblasts 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 drastically 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. [Display omitted] •LepR-lineage stromal cells are the major source of myofibroblasts in PMF•Gli1-lineage cells contribute little to myofibroblasts and are not required for PMF•Coordinated stromal remodeling promotes pathogenesis in the PMF bone marrow•Sox10+ glial cells expand in PMF and their ablation ameliorates PMF phenotypes Ding and colleagues demonstrate that LepR-lineage cells are the major source, whereas Gli1-lineage cells contribute to a minor portion, of myofibroblasts in PMF. They found an expansion of bone marrow Sox10+ glial cells in PMF and show that ablation of bone marrow glial cells ameliorates PMF phenotypes in the bone marrow.