2. Academic Validation
  3. Systematic dissection of coordinated stromal remodeling identifies Sox10+ glial cells as a therapeutic target in myelofibrosis

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

  • Cell Stem Cell. 2023 Jun 1;30(6):832-850.e6. doi: 10.1016/j.stem.2023.05.002.
Shawn M Sarkaria 1,  Junsong Zhou 2,  Suying Bao 3,  Wenqi Zhao 2,  Yinshan Fang 4,  Jianwen Que 4,  Govind Bhagat 5,  Chaolin Zhang 3,  Lei Ding 6
Affiliations

Affiliations

  • 1 Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Division of Hematology and Medical Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 2 Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 3 Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 4 Division of Digestive and Liver Diseases, Columbia Center for Human Development, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 5 Division of Hematopathology, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 6 Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: ld2567@cumc.columbia.edu.
PMID: 37267917 DOI: 10.1016/j.stem.2023.05.002
Abstract

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.

Keywords

Gli1; LepR; glial cells; hematopoietic stem cells; lineage tracing; mesenchymal stromal cells; microenvironmental niche; myelofibrosis; single-cell RNA sequencing.

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