Abstract
BackgroundUpon inflammation, myeloid cell generation in the bone marrow (BM) is broadly enhanced by the action of induced cytokines which are produced locally and at multiple sites throughout the body.MethodsUsing microarray studies, we found that Angptl4 is upregulated in the BM during systemic inflammation.ResultsRecombinant murine Angptl4 (rmAngptl4) stimulated the proliferation of myeloid colony-forming units (CFUs) in vitro. Upon repeated in vivo injections, rmAngptl4 increased BM progenitor cell frequency and this was paralleled by a relative increase in phenotypically defined granulocyte-macrophage progenitors (GMPs). Furthermore, in vivo treatment with rmAngptl4 resulted in elevated platelet counts in steady-state mice while allowing a significant acceleration of reconstitution of platelets after myelosuppressive therapy. The administration of rmAngptl4 increased the number of CD61+CD41low-expressing megakaryocytes (MK) in the BM of steady-state and in the spleen of transplanted mice. Furthermore, rmAngptl4 improved the in vitro differentiation of immature MKs from hematopoietic stem and progenitor cells. Mechanistically, using a signal transducer and activator of transcription 3 (STAT3) reporter knockin model, we show that rmAngptl4 induces de novo STAT3 expression in immature MK which could be important for the effective expansion of MKs after myelosuppressive therapy.ConclusionWhereas the definitive role of Angptl4 in mediating the effects of lipopolysaccharide (LPS) on the BM has to be demonstrated by further studies involving multiple cytokine knockouts, our data suggest that Angptl4 plays a critical role during hematopoietic, especially megakaryopoietic, reconstitution following stem cell transplantation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0152-2) contains supplementary material, which is available to authorized users.
Highlights
Upon inflammation, myeloid cell generation in the bone marrow (BM) is broadly enhanced by the action of induced cytokines which are produced locally and at multiple sites throughout the body
Since previous studies had already implicated a potential role of angiopoietin-like family members affecting hematopoiesis [21, 22], we focused on the characterization of angiopoietin-like 4 (Angptl4) expression during inflammatory conditions and its effects on hematopoiesis in vitro and in vivo
Our results show that Angptl4 can regulate myeloid cell proliferation at the level of HPCs, and Angptl4 should be added to the growing list of early-acting cytokines such as IL-3 and IL-6
Summary
Myeloid cell generation in the bone marrow (BM) is broadly enhanced by the action of induced cytokines which are produced locally and at multiple sites throughout the body. During steady-state conditions, hematopoiesis is controlled by the coordinated action of a complex interplay of supporting growth factors and the signals they deliver through hematopoietic cytokine receptors expressed at the surface of HSPCs [2, 3]. These growth factors are produced in the bone marrow (BM) microenvironment or at multiple sites throughout the body from where they reach their target cells in the BM via the bloodstream [2, 4]. In response to gram-negative infections, emergency myelopoiesis is mediated by TLR4expressing non-hematopoietic cells, which sense systemic lipopolysaccharide and by secreting myeloid cytokines such as G-CSF, induce an adequate myelopoietic response within the BM [9]
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