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Bone marrow fibrosis is the most extensive matrix remodeling of the microenvironment and can include de novo formation of bone (osteosclerosis). Spatiotemporal information on the contribution of distinct bone marrow niche populations to this process is incomplete. We demonstrate that fibrosis‐inducing hematopoietic cells cause profibrotic reprogramming of perivascular CXCL12‐abundant reticular (CAR) progenitor cells, resulting in loss of their hematopoiesis‐support and upregulation of osteogenic and pro‐apoptotic programs. In turn, peritrabecular osteolineage cells (OLCs) are activated in an injury‐specific, Wnt‐dependent manner, comparable to skeletal repair. OLCs fuel bone marrow fibrosis through their expansion and skewed differentiation, resulting in osteosclerosis and expansion of Ly6a+ fibroblasts. NCAM1 expression marks peritrabecular OLCs and their expansion into the central marrow is specific for fibrosis in mice and patients. Peritrabecular stromal β‐catenin expression is linked to fibrosis in patients, and inhibition of Wnt signaling reduces bone marrow fibrosis and osteosclerosis, possibly being a clinically relevant therapeutic target.

The maintenance of a basal immunoinflammatory signature in hematopoietic stem/progenitor cells (HSPCs) constitutes a fundamental regulatory axis governing hematopoietic competence and immune effector generation. While epigenetic repressors constrain this inflammatory phenotype, the molecular amplifiers that preserve this critical state remain undefined. Through integrated single-cell transcriptomic/epigenomic profiling and functional interrogation, we identify Setd2-mediated H3K36me3 as an indispensable epigenetic amplifier sustaining baseline inflammation in murine HSPCs. Setd2 ablation specifically eliminated interferon (IFN)-enriched HSPC subpopulations and attenuated inflammatory signaling cascades. Functionally, Setd2-deficient HSPCs exhibited impaired IFNγ responsiveness, compromised B-lymphopoiesis, and diminished reconstitution capacity due to Lin−c-Kit+Sca1high cell depletion. Paradoxically, Setd2 loss conferred resistance to IFNγ-induced HSPCs exhaustion, which may contribute to the maintenance of Setd2-deficient HSPCs in our myelodysplastic syndrome (MDS) model under the inflammatory milieu. Mechanistically, Setd2 sustained chromatin accessibility and enhancer (H3K27ac) activity at inflammatory gene loci. This work delineates a critical link between Setd2-mediated chromatin regulation, baseline inflammation, HSPC function, and immune competence, providing insights into inflammatory dysregulation in hematopoietic malignancies like MDS.

Alongside their well-established role in hemostasis, platelets are key modulators of immune cell function. This is particularly the case for macrophages, as platelets can either promote or dampen macrophage activation in a context-specific manner. Whilst the role of platelets in modulating classical (M1) macrophage activation following bacterial challenge is relatively well understood, whether platelets control other macrophage responses is less clear. We investigated the role of platelets in type 2 inflammation using a mouse model of chronic schistosomiasis. Schistosome infection caused thrombocytopenia which was not fully reversed after drug-induced parasite death. Reduced platelet levels in infection were coincident with lower levels of systemic TPO and extensive liver damage caused by parasite eggs. Infection also reduced the ploidy and size (but not number) of bone marrow megakaryocytes, which was associated with reduced platelet output. We show schistosome infection accelerated platelet clearance and promoted the formation of platelet-leukocyte aggregates. This was particularly the case for liver macrophages and monocytes. Phenotypic analysis shows that platelet-associated liver macrophages had a distinct activation phenotype that included elevated expression of the alternative (M2) activation marker RELMα. Despite this, in vitro studies indicated that platelets do not directly promote macrophage alternative activation. Similarly, whilst in vivo pharmacological treatment with a TPO mimetic enhanced platelet numbers and platelet-leukocyte aggregates, this did not alter macrophage phenotype. Conversely, antibody-mediated depletion of platelets or use of platelet-deficient mice both led to extensive bleeding following infection which impacted host survival. Together, these data indicate that whilst platelets are essential to prevent excessive disease pathology in schistosomiasis, they have a more nuanced role in myeloid cell activation and type 2 immune responses. Author summaryPlatelets are the second most abundant blood cell and are best known for their role in stopping bleeding after blood vessel damage. More recent studies have revealed another important function of platelets is their ability to control immune cell activation. Here, we investigate the role of platelets in immune responses to schistosomes, parasitic worms that cause the disease schistosomiasis that affects hundreds of millions worldwide. Schistosome worms live in our blood vessels and release large numbers of eggs that must exit the blood and move through our tissues to exit the body for onward transmission. However, a large number of eggs become trapped in different organs causing inflammation and disease pathology. We find that schistosome infection reduces the numbers of platelets in the blood of laboratory mice. Platelets are taken up by liver macrophages, and whilst these macrophages have a distinct activation profile compared to other cells, platelets themselves do not cause these changes. However, platelets are essential to survive schistosomiasis due to excessive bleeding in their absence. Together, this work shows that platelets are key to surviving schistosome infection but this reflects more their role in preventing bleeding rather than controlling immune cell function.