Angptl4 is upregulated under inflammatory conditions in the bone marrow of mice, expands myeloid progenitors, and accelerates reconstitution of platelets after myelosuppressive therapy

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.

Global transcriptomic profiling of the bone marrow stromal microenvironment during postnatal development, aging and inflammation

“…Strikingly, and in contrast to what has been proposed (Maryanovich et al, 2018), aged CARc did not exhibit changes in expression of crucial prohematopoietic factors such as Cxcl12, Scf or Angpt1. Nonetheless, we did note significant downregulation of Wnt-inhibitory factor (Wif1), Angptl4 and Npy, associated to the modulation of HSC function ( Figure 4I and 5E) (Park et al, 2015;Schumacher et al, 2015;Singh et al, 2017). Moreover, aging was linked to a repression of gene categories associated to ECM organization, collagen formation and adhesive interactions, which was strongest in mesenchymal cells but also evident in ECs.…”

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

“…(22) We recently reported that A1AT purified from human plasma binds polyunsaturated fatty acids (FAs) like α-linoleic and oleic acid, and that only FA-bound forms of A1AT increase the expression and release of ANGPTL4 in human bloodadherent monocytic cells and in primary human lung microvascular endothelial cells. (23,24) The above functional differences between FA-free and FA-bound forms of A1AT led us to hypothesize that these 2 forms may express distinct immunomodulatory activities during neutrophil activation. Neutrophils account for about 50-75 % of circulating leukocytes, and during inflammation they are the first immune defense cells to arrive and function via multiple intra-and extracellular mechanisms.…”

A peptide from Testudo horsfieldii tortoise spleen as a potential helper for reducing acute radiation syndrome

“…3 Moreover, it is essential to maintain the functional capabilities of the BM during storage prior to transplantation. [4][5][6][7][8] The characterization of many cytokines involved in the control of hematopoiesis led to intense investigation into their potential use "in vitro" to expand progenitor cell numbers. [9][10][11][12] The collected data suggests that this may be an effective therapeutic strategy to reduce relapse after transplantation; however, selection and expression of cytokines must be carefully considered to minimize adverse effects on hematopoiesis.…”