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

Journal of Hematology & Oncology

Patrick Ziegler²  Tim H. Brümmendorf¹  Gerhard Müller-Newen⁹  Valeria Poli³  Annalisa Camporeale³  Dieter Görtz⁹  Michael Vogt⁸  Antons Martincuks⁹  Matthias B. Stope⁵  Lars-Ove Brandenburg⁴  Susanne Ziegler¹  Jasmin Stahlschmidt¹  Till Braunschweig⁶  Bernd Denecke⁷  Anne Schumacher¹ 

[1] Department of Oncology, Hematology and Stem Cell Transplantation, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, Aachen, 52074, Germany;Institute for Occupational and Social Medicine, Aachen University, Aachen, Germany;Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, 10126, Italy;Department of Anatomy and Cell Biology, RWTH Aachen University, Wendlingweg 2, Aachen, 52074, Germany;Department of Urology, University Medicine Greifswald, Greifswald, Germany;Institute of Pathology, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, Aachen, 52074, Germany;Interdisciplinary Center for Clinical Research IZKF Aachen, RWTH Aachen University Hospital, Aachen, Germany;Institute for Laboratory Animal Science, University Hospital, Pauwelsstrasse 30, Aachen, 52074, Germany;Department of Biochemistry and Molecular Biology, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, Aachen, 52074, Germany

关键词: STAT3;    Myelosuppressive therapy;    Platelet reconstitution;    Angptl4;    Inflammatory conditions;   

Others  :  1221100
DOI  :  10.1186/s13045-015-0152-2

 received in 2014-12-17, accepted in 2015-05-07,  发布年份 2015

【 摘 要 】

Background

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.

Methods

Using microarray studies, we found that Angptl4 is upregulated in the BM during systemic inflammation.

Results

Recombinant 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⁺CD41^low-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.

Conclusion

Whereas 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.

【 授权许可】

   
2015 Schumacher et al.

【 图 表 】

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