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

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.

[Changes in ultrastructure and bone morphogenetic protein expression in reconstructed mandibular condylar cartilage under continuous mandibular advancement in adult rats].

OBJECTIVE: This study investigated the reconstructed mandibular condylar cartilage and the ultrastructural variations in mandibular condylar cartilage in adult rats as a result of mandibular advancement. METHODS: Thirty 9-week-old male Sprague-Dawley rats were randomly divided into experimental and control groups. Rats in the experimental group were subjected to mandibular advancement. Rats were sacrificed on days 3, 7, 14, 21, 30. Sections were cut from condyles, and bone morphogenetic protein-2 (BMP-2) expression in condylar cartilage was examined through immunohistochemical analysis. Condylar cartilage samples were harvested, and ultrastructural changes in these samples were observed under Micro-CT and transmission electron microscope. RESULTS: Compared with the control group, the experimental group obviously displayed cartilage hyperplasia in the middle and rear of the condyle. Moreover, the number of BMP-2-positive cells in condylar cartilage and the gray value gradually increased in the experimental group on day 7 of the intervention. Ultrastructural changes, such as karyopyknosis, reduced microfilaments around the nucleus, reduction in size or even disappearance of lipid droplets, swelling of endoplasmic reticulum compartments, broadened and increased extracellular matrix, were observed in the condylar hypertrophic chondrocytes. Micro-CT revealed that the trabecula and the newly formed bone gradually thickened. CONCLUSIONS: Hypertrophic remodeling of the condylar cartilage and high BMP-2 expression are observed in adult rats as a result of continuous mandibular advancement.