Hematopoietic stem cell loss and hematopoietic failure in severe aplastic anemia is driven by macrophages and aberrant podoplanin expression
EHA Library. McCabe A. Sep 1, 2018; 234225 Topic: 4Bc Mobilization, collection and manipulation of hematopoeitic stem cells
Amanda McCabe
Amanda McCabe
Contributions
Journal Abstract

Co-Authors: Julianne N.P. Smith, Angelica Costello, Jackson Maloney, Divya Katikaneni, Katherine C. MacNamara

Abstract: Severe aplastic anemia (SAA) results from profound hematopoietic stem cell loss. T cells and interferon gamma (IFNγ) have long been associated with SAA, yet the underlying mechanisms driving hematopoietic stem cell loss remain unknown. Using a mouse model of SAA, we demonstrate that IFNγ-dependent hematopoietic stem cell loss required macrophages. IFNγ was necessary for bone marrow macrophage persistence, despite loss of other myeloid cells and hematopoietic stem cells. Depleting macrophages or abrogating IFNγ signaling specifically in macrophages did not impair T-cell activation or IFNγ production in the bone marrow but rescued hematopoietic stem cells and reduced mortality. Thus, macrophages are not required for induction of IFNγ in SAA and rather act as sensors of IFNγ. Macrophage depletion rescued thrombocytopenia, increased bone marrow megakaryocytes, preserved platelet-primed stem cells, and increased the platelet-repopulating capacity of transplanted hematopoietic stem cells. In addition to the hematopoietic effects, SAA induced loss of non-hematopoietic stromal populations, including podoplanin-positive stromal cells. However, a subset of podoplanin-positive macrophages was increased during disease, and blockade of podoplanin in mice was sufficient to rescue disease. Our data further our understanding of disease pathogenesis, demonstrating a novel role for macrophages as sensors of IFNγ, thus illustrating an important role for the microenvironment in the pathogenesis of SAA.

Article Number: 1451

Doi: 10.3324/haematol.2018.189449

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