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

ABSTRACT: Upon inflammation, myeloid cell generation in the bone marrow (BM) is broadly enhanced by the action of induced cytokines, which are produced locally or at multiple sites throughout the body. Using microarray studies, we show that Angptl4 is a predominantly upregulated cytokine in the BM during systemic inflammatory conditions. Functionally we found recombinant murine Angptl4 (rmAngptl4) to stimulate the proliferation of myeloid 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 and a significantly accelerated reconstitution of platelets in post-transplanted mice after myelosuppressive therapy. In contrast, transplantation of BM cells from donor mice pre-treated with rmAngptl4 had no effect on the recovery of platelets. The administration of rmAngptl4 additionally increased the number of CD61+CD41low-expressing megakaryocytes (MKs) in the BM of steady-state and in the spleen of transplanted mice as well as after in vitro MK-differentiation from hematopoietic stem and progenitor cells. Furthermore, using a stat3 reporter knockin model, we show that rmAngptl4 induces de novo stat3 expression in immature MKs which could be important for the effective expansion of MKs after myelosuppressive therapy. In summary our data suggest that Angptl4 plays a complementary role in hematopoiesis during emergency situations like sepsis. The use of Angptl4 in the setting of autologous stem cell transplantation could represent a potential approach for accelerating the reconstitution of megakaryopoiesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE55161 | GEO | 2017/02/11

SECONDARY ACCESSION(S): PRJNA238662

REPOSITORIES: GEO

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Project description:The hematopoietic system gives rise to a heterogeneous population of terminally differentiated cells that reside in the bone marrow (BM) to fulfill their roles in immunity, blood clotting and tissue oxygenation. Hematopoietic stem and progenitor cells are at the apex of a hierarchically organized maturation cascade constantly replenishing the pool of differentiated cells to maintain blood cell homeostasis. The bone marrow microenvironment is functionally compartmentalized by heterogeneous niche cells that provide physical and soluble signals to spatio-temporally organize hematopoiesis. Megakaryocytes (MKs) are niche cells of hematopoietic origin that support hematopoietic stem cell (HSCs) homeostasis and generate circulating platelets. Platelet production involves the release of MK fragments while their cell body is entirely consumed in a process termed thrombopoiesis. Consequently, replenishment of fragmented MKs from MK progenitors (termed megakaryopoiesis) is required to ensure sufficient platelet production, but also to maintain MK homeostasis within the HSC niche. Here, we used intravital imaging of the megakaryocytic lineage to identify the spatio-temporal patterns of megakaryopoiesis during steady state and thrombocytopenia. We show that MK consumption during thrombopoiesis is compensated by immediate and local proliferation of MK progenitors. MK homeostasis is controlled by plasmacytoid dendritic cells (pDCs) that scan the BM and secrete Interferon alpha (INFa) upon detection of exhausted megakaryocytes to trigger megakaryopoiesis. We identified local pDC-derived INFa release as a physiological inflammatory stimulus of the bone marrow niche that synchronizes megakaryopoiesis and thrombopoiesis to maintain homeostasis of MKs and platelets in steady state and under stress. Viral infection with SARS-CoV-2 can manipulate pDC-driven MK proliferation leading to inappropriate megakaryopoiesis, which has been associated with thrombotic complications during COVID-19.

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

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