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.
Health professions students with higher levels of religiosity and lower levels of self-reported familiarity with various religious perspectives on sex reported less positive attitudes toward LGBT individuals. Results suggest that personal factors may be important to address in interprofessional curriculum related to LGBT patient care. Self-report biases and other factors may limit the accuracy and generalizability of the findings.
Cervical kyphotic deformity can be a debilitating condition with symptoms ranging from mechanical neck pain, radiculopathy, and myelopathy to impaired swallowing and horizontal gaze. Surgical correction of cervical kyphosis has the potential to halt progression of neurological and clinical deterioration and even restore function. There are various operative approaches and deformity correction techniques. Choosing the optimal strategy is predicated on a fundamental understanding of spine biomechanics. Preoperative characterization of cervical malalignment, assessment of deformity rigidity, and defining postoperative clinical and radiographic objectives are paramount to formulating a surgical plan that balances clinical benefit with morbidity. This review of cervical deformity treatment provides an overview of the biomechanics of cervical kyphosis, radiographic classification, algorithm-based management, surgical techniques, and current surgical outcome studies.
Ewing’s sarcomas are highly aggressive round cell tumors of bone and soft tissues that afflict children and young adults. The majority of these tumors harbor the t(11;22) translocation and express the fusion protein EWS-FLI. Modern molecular profiling experiments indicate that Ewing’s tumors originate from mesenchymal precursors in young individuals. EWS-FLI alters the morphology of mesenchymal cells and prevents lineage specification; however, the molecular mechanisms for differentiation arrest are unclear. We recently showed that EWS-FLI binds Runx2, a master regulator of osteoblast differentiation. In this report, we demonstrate that FLI sequences within EWS-FLI are responsible for interactions with Runx2. EWS-FLI blocks the expression of osteoblastic genes in a multipotent progenitor cell line that requires Runx2 to integrate bone morphogenic protein (Bmp)2 signaling while increasing proliferation and altering cell morphology. These results demonstrate that EWS-FLI blocks the ability of Runx2 to induce osteoblast specification of a mesenchymal progenitor cell. Disrupting interactions between Runx2 and EWS-FLI1 may promote differentiation of the tumor cell.
RUNX transcription factors reside in the nuclear matrix where they integrate numerous signaling pathways to regulate gene expression and affect tissue development, regeneration, and tumorigenesis. An affinity purification and proteomic experiment was performed to identify novel Runx2 binding partners. The interactions between Runx2 and two nuclear factors identified in this screen, Ddx5 and CoAA, were previously described. Co-activator activator (CoAA) bound the DNA binding domain of Runx2 and prevented Runx-driven gene expression. The YxxQ motif in CoAA was required for Runx2 interactions. Members of the FET/TET family of proteins, including FUS/TLS and EWSR1, contain a similar motif and were hypothesized to interact with Runx2. Here we provide evidence that FUS/TLS, EWSR1 and the Ewing's sarcoma t(12;21) fusion protein EWS-FLI, bind Runx2 and alter its transcriptional activity. Potential roles of protein complexes containing FET/TET and RUNX family members during tumor formation and mesenchymal progenitor cell differentiation are discussed.
Various cell types cooperate to create a highly organized and dynamic micro-environmental niche in the bone marrow. Over the past several years, the field has increasingly recognized the critical roles of the interplay between bone marrow environment and hematopoietic cells in normal and deranged hematopoiesis. These advances rely on several new technologies that have allowed us to characterize the identity and roles of these niches in great detail. Here, we review the progress of the last several years, list some of the outstanding questions in the field and propose ways to target the diseased environment to better treat hematologic diseases. Understanding the extrinsic regulation by the niche will help boost hematopoiesis for regenerative medicine. Based on natural development of hematologic malignancies, we propose that combinatory targeting the niche and hematopoietic intrinsic mechanisms in early stages of hematopoietic malignancies may help eliminate minimal residual disease and have the highest efficacy.
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