Haematopoietic stem cells (HSCs) maintain balanced self-renewal and differentiation, but how these functions are precisely regulated is not fully understood. N6-methyladenosine (m6A) mRNA methylation has emerged as an important mode of epitranscriptional gene expression regulation affecting many biological processes. We show that deleting the m6A methyltransferase, Mettl3, from the adult haematopoietic system led to an accumulation of HSCs in the bone marrow and marked reduction of reconstitution potential due to a blockage of HSC differentiation. Interestingly, deleting Mettl3 from myeloid cells using Lysm-cre did not impact myeloid cell number or function. m6A sequencing revealed 2,073 genes with significant m6A modification in HSCs. Myc was identified as a direct target of m6A in HSCs. Mettl3-deficient HSCs failed to up-regulate MYC expression upon stimulation to differentiate and enforced expression of Myc rescued differentiation defects of Mettl3-deficient HSCs. Our results revealed a key role of m6A in governing HSC differentiation.

Bone marrow fibrosis is a critical component of primary myelofibrosis (PMF). But the origin of myofibroblasts that drive fibrosis is unknown. Using genetic fate mapping we found that bone marrow Leptin receptor (Lepr) – expressing mesenchymal stromal lineage cells expanded extensively and were the fibrogenic cells in PMF. These stromal cells down-regulated the expression of key haematopoietic stem cell (HSC)- supporting factors and up-regulated genes associated with fibrosis and osteogenesis, indicating fibrogenic conversion. Administration of imatinib or conditional deletion of platelet-derived growth factor receptor a (Pdgfra) from Lepr+ stromal cells suppressed their expansion and ameliorated bone marrow fibrosis. Conversely, activation of the PDGFRa pathway in bone marrow Lepr+ cells led to expansion of these cells and extramedullary haematopoiesis, features of PMF. Our data identify Lepr+ stromal lineage cells as the origin of myofibroblasts in PMF and suggest that targeting PDGFRa signaling could be an effective way to treat bone marrow fibrosis.

Hematopoietic stem cell (HSC) maintenance depends on extrinsic cues. Currently, only local signals arising from the bone marrow niche have been shown to maintain HSCs. However, it is not known whether systemic factors also sustain HSCs. We assessed the physiological source of thrombopoietin (TPO), a key cytokine required for maintaining HSCs. Using knock-in mice, we showed that TPO is expressed by hepatocytes but not by bone marrow cells. Deletion of from hematopoietic cells, osteoblasts, or bone marrow mesenchymal stromal cells does not affect HSC number or function. However, when is deleted from hepatocytes, bone marrow HSCs are depleted. Thus, a cross-organ factor, circulating TPO made in the liver by hepatocytes, is required for bone marrow HSC maintenance. Our results demonstrate that systemic factors, in addition to the local niche, are a critical extrinsic component for HSC maintenance.

VPA could not only suppress tumor progression but also provide a novel promising therapeutic choice in combination with a receptor-targeted cytotoxic conjugate via activating the specific receptor.

The liver maintains hematopoietic stem cells (HSCs) during development. However, it is not clear what cells are the components of the developing liver niche in vivo. Here, we genetically dissected the developing liver niche by systematically determining the cellular source of a key HSC niche factor, stem cell factor (SCF). Most HSCs were closely associated with sinusoidal vasculature. Using Scfgfp knockin mice, we found that Scf was primarily expressed by endothelial and perisinusoidal hepatic stellate cells. Conditional deletion of Scf from hepatocytes, hematopoietic cells, Ng2+ cells, or endothelial cells did not affect HSC number or function. Deletion of Scf from hepatic stellate cells depleted HSCs. Nearly all HSCs were lost when Scf was deleted from both endothelial and hepatic stellate cells. The expression of several niche factors was down-regulated in stellate cells around birth, when HSCs egress the developing liver. Thus, hepatic stellate and endothelial cells create perisinusoidal vascular HSC niche in the developing liver by producing SCF.