Neoplastic fibrocytes play an essential role in bone marrow fibrosis in Jak2V617F-induced primary myelofibrosis mice

Abstract

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by clonal myeloproliferation, progressive bone marrow (BM) fibrosis, splenomegaly, and anemia. BM fibrosis was previously thought to be a reactive phenomenon induced by mesenchymal stromal cells that are stimulated by the overproduction of cytokines such as transforming growth factor (TGF)-β1. However, the involvement of neoplastic fibrocytes in BM fibrosis was recently reported. In this study, we showed that the vast majority of collagen- and fibronectin-producing cells in the BM and spleens of Jak2V617F-induced myelofibrosis (MF) mice were fibrocytes derived from neoplastic hematopoietic cells. Neoplastic monocyte depletion eliminated collagen- and fibronectin-producing fibrocytes in BM and spleen, and ameliorated most characteristic MF features in Jak2V617F transgenic mice, including BM fibrosis, anemia, and splenomegaly, while had little effect on the elevated numbers of megakaryocytes and stem cells in BM, and leukothrombocytosis in peripheral blood. TGF-β1, which was produced by hematopoietic cells including fibrocytes, promoted the differentiation of neoplastic monocytes to fibrocytes, and elevated plasma TGF-β1 levels were normalized by monocyte depletion. Collectively, our data suggest that neoplastic fibrocytes are the major contributor to BM fibrosis in PMF, and TGF-β1 is required for their differentiation.

Early and late stage MPN patients show distinct gene expression profiles in CD34+ cells

“…TIMD4 that was upregulated in all subtypes was observed to induce T cell exhaustion in cancer and promote colorectal cancer by activating angiogenesis and recruitment of tumor-associated macrophages [70,71]. In PMF, TIMD4 was reported to recruit monocytes/macrophages to the BM [72]. VCAM1, which was also elevated in our GEA, contributes to the clinical phenomena of thrombosis and extramedullary hematopoiesis occurring in MPN patients [73].…”

ER‐anchored CRTH2 antagonizes collagen biosynthesis and organ fibrosis via binding LARP6

“…Mouse fibrocytes were harvested and cultured as previously described (Phillips et al , 2004; Ozono et al , 2021). Briefly, mononuclear cells were isolated by Lympholyte‐Mammal (Cedarlane, Burlington, NC, USA) from bone marrow cells and then cultured in DMEM supplemented with 20% FCS, penicillin, streptomycin, and l ‐glutamine for 6 days.…”

Cellular Heterogeneity of Mesenchymal Stem/Stromal Cells in the Bone Marrow

“…MPN, a clonal disorder of HSCs and the ensuing fibrosis, is a secondary effect caused by the release of cytokines from progenitor cells ( Jacobson et al, 1978 ). Abnormal production of growth factors (PDGF, FGF, VEGF, and TGF-β1) plays important roles the pathological changes associated with MPNs ( Ciurea et al, 2007 ; Tomuleasa et al, 2018 ; Ozono et al, 2020 ). Excessive release of growth factors stimulates fibroblasts thereby inducing fibrosis and unbalanced osteoblast proliferation, resulting in osteosclerosis and neoangiogenesis ( Chagraoui et al, 2003 ).…”