Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis

Abstract

Summary Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. We aimed to generate a comprehensive map of the stroma in MPNs/MFs on a single-cell level in murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-fibrotic and acquisition of a pro-fibrotic and inflammatory phenotype in the fibrotic stage. The expression of the alarmin complex S100A8/S100A9 in MSC marked disease progression toward the fibrotic phase in murine models and in patient stroma and plasma. Tasquinimod, a small-molecule inhibiting S100A8/S100A9 signaling, significantly ameliorated the MPN phenotype and fibrosis in JAK2V617F-mutated murine models, highlighting that S100A8/S100A9 is an attractive therapeutic target in MPNs.

Single-Cell Atlas Reveals Fatty Acid Metabolites Regulate the Functional Heterogeneity of Mesenchymal Stem Cells

“…In our work, we performed 10x scRNA-seq on bone marrow non-hematopoietic (CD45 − , Ter-119 − ), non-endothelial (CD31 − ), and PDGFRα + CD51 + MSCs. In line with previous studies (Pacini and Petrini, 2014;Baccin et al, 2020;Leimkuhler et al, 2020), we identified lineage-committed MSCs, including adipogenic, osteogenic, chondrogenic, angiogenic, and immunomodulating MSCs. Furthermore, we identified a pre-MSC population, which enriched prelineage commitment genes involved in protein transport, nuclear transport, and ribosome biogenesis pathways, such as Rps24, Rpl35a, and Ndufb3 (Choesmel et al, 2008;Narla et al, 2011;Alston et al, 2016) and clustering at the root of the unsupervised pseudotime trajectory.…”

“…Studies using RNA fluorescence in situ hybridization (FISH) (Cote et al, 2016) and fluorescent probes indicate that canonical markers are tenuously linked to the differentiated phenotypes, and it is difficult to use single markers to predict functional potential. Recent advanced single-cell studies have further explored the heterogeneity of bone marrow MSCs with distinct differentiation potential (Baryawno et al, 2019;Leimkuhler et al, 2020). Furthermore, researchers also identified an IL-10 regulated metabolically active mature adipocyte subtype from subcutaneous adipose tissue (Rajbhandari et al, 2019) and Runx2 + /Gli1 + cells in the adult mouse incisor, which maintains Gli1 + MSCs (Chen et al, 2020).…”

“…Immunomodulating MSCs were constituted by clusters 7, 10, and 11, which enriched pathways associated with leukocyte proliferation and myeloid cell homeostasis (Figure 1E). Furthermore, these immunomodulating MSCs overlapped with other MSC subpopulations and published bone marrow MSCs (Baryawno et al, 2019;Leimkuhler et al, 2020) but not with immune cells (Choi et al, 2019) (Figure 1G). In line with this, immunomodulating MSCs did not express any immune cell markers, such as T cells, B cells, NK cells, and macrophages (Supplementary Figure 1B).…”

Molecular pathogenesis of the myeloproliferative neoplasms

“…The interaction between the malignant clone and stromal cells by means of pro-inflammatory and cytokine signalling is a key determinant in the formation of a fibrotic phenotype. Myofibroblasts responsible for the deposition of collagen are derived from multipotent mesenchymal progenitor stromal cells [ 126 – 128 ]. These myofibroblasts evolve over time, undergoing a maldifferentiation process to lose ability to support haematopoietic tissue and contribute to marrow fibrosis.…”

“…These myofibroblasts evolve over time, undergoing a maldifferentiation process to lose ability to support haematopoietic tissue and contribute to marrow fibrosis. The presence of the malignant haematopoietic clone and resulting inflammatory milieu provide a continuous drive for myofibroblast differentiation and vicious cycle of fibrosis [ 128 ]. Removing Gli1 + mesenchymal stromal cells or interfering with PDGFRA signalling in these cells can ameliorate the fibrotic phenotype [ 126 , 127 ].…”