Angiopoietin-like 4 als Mediator der reaktiven Hämatopoese
- Angiopoietin-like 4 as mediator of inflammatory hematopoiesis
Schumacher, Anne; Brümmendorf, Tim Henrik (Thesis advisor); Schirawski, Jan (Thesis advisor)
Dissertation / PhD Thesis
Aachen, Techn. Hochsch., Diss., 2014
Blood cell production (hematopoiesis) is hierarchically organized with hematopoietic stem cells at the top, which ensure via both self-renewal and differentiation to multipotent and stepwise blood lineage-committed progenitors the continuous production of all different blood cells throughout the life time of an individual. This process is tightly controlled by the concerted action of hematopoiesis supporting cytokines such as G-CSF, GM-CSF or IL-6, which regulate hematopoiesis during steady state and emergency situations. During inflammatory conditions like sepsis when innate immune system cells are in high demand, these cytokines are upregulated, bone marrow myelopoiesis is enhanced and myeloid colony-forming progenitor cells and granulocytes increase in circulation. However, alternative pathways are likely to exist as mice with single or combined deficiencies for G-CSF, GM-CSF and IL-6 or G-CSF and GM-CSF are still able to mount reactive neutrophilia responses during inflammatory conditions. The topic of this work is the evaluation of the candidate-protein Angiopoietin-like 4 (Angptl 4) as a potential new mediator of inflammatory myelopoiesis. Among known candidates Angptl-4 is predominantly upregulated in the bone marrow (BM) of lipopolysaccharid (LPS)-treated mice and mice with generalized infection with Gram-positive Streptococcus pneumoniae. Moreover human and murine bone marrow derived mesenchymal stem cells (MSC), which are known to support hematopoiesis via secretion of promyeloic cytokines, respond to LPS stimulation with Angptl 4 production. Recombinant murine Angptl 4 (rmAngptl 4) stimulates the proliferation of myeloid colony-forming units (CFU) in vitro and in vivo. Repeated intravenous injections of rmAngptl 4 increase BM progenitor cell frequency and result in an expansion of phenotypically defined granulocyte-macrophage progenitors (GMPs) in mouse BM. Furthermore Angptl 4 accelerates early megakaryopoiesis. rmAngptl4 improved the in vitro differentiation of immature MKs from hematopoietic stem and progenitor cells and leads to increased expression of transcription factors of megakaryopoiesis and the surface antigene CD61 but not CD41. In vivo treatment with rmAngptl 4 results in elevated platelet counts both in untreated animals and after myelosuppressive therapy. In summary, these data suggest that Angptl 4 plays a complementary role on hematopoiesis during emergency situations like sepsis. In a model for Angptl 4-dependent inflammatory hematopoiesis MSC sense conserved pathogenic signals like LPS during the course of an extended infection and respond by secretion of Angptl 4 and other promyeloic cytokines. Angptl 4 then increases the production of GMPs which develop into mature immune cells and fight pathogens at the sites of infections.On the other hand Angptl 4 supports megakaryopoiesis in order to overcome thrombocytopenia during severe sepsis.