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Abstract
Aplastic anemia (AA) is characterized by bone marrow (BM) hypocellularity, resulting in peripheral cytopenias. An antigen-driven and likely auto-immune dysregulated T-cell homeostasis results in hematopoietic stem cell injury, which ultimately leads to the pathogenesis of the acquired form of this disease. Auto-immune and inflammatory processes further influence the disease course as well as response rate to therapy, mainly consisting of intensive immunosuppressive therapy and allogeneic hematopoietic cell transplantation. Bone marrow hematopoietic stem and progenitor cells are strongly regulated by the crosstalk with the surrounding microenvironment and its components like mesenchymal stromal cells, also consistently altered in AA. Whether latter is a contributing cause or rather consequence of the disease remains an open question. Overall, niche disruption may contribute to disease progression, sustain pancytopenia and promote clonal evolution. Here we review the existing knowledge on BM microenvironmental changes in acquired AA and discuss their relevance for the pathogenesis and therapy.
Highlights
Acquired aplastic anemia (AA) is characterized by a hypoplastic, fatty bone marrow (BM) with profound reductions in hematopoietic stem/progenitor cells (HSCs/HPCs) that lead to defective mature blood cell production and peripheral pancytopenia [1,2,3]
Because of a quantitative Mesenchymal stem cells (MSCs) impairment in patients with acquired AA, it is tempting to speculate that bone marrow transplantations may yield better results compared to peripheral blood as stem cell source because they provide higher numbers of co-transplanted MSCs and supporting non-hematopoietic cell populations, which may promote niche reconstitution and thereby indirectly support nascent hematopoiesis in AA patients treated with allogeneic transplantations. allo-HCT, allogeneic hematopoietic cell transplantation; AA, aplastic anemia; BM, bone marrow; BMF, bone marrow failure; hematopoietic stem/progenitor cells (HSPC), hematopoietic stem and progenitor cells; MSC, mesenchymal stem cells; PB, peripheral blood; SDS, Shwachman-Diamond syndrome
Several mechanisms may influence the restoration of the BM niche in case functional non-hematopoietic progenitor cells are transplanted next to HSCs/HPCs with BM vs. PB transplants [68,69,70]: [1] Donor-derived BM-MSCs [71] may engraft and differentiate to niche cells, vascular endothelial cells and perivascular cells after HCT; [2] CD34+ progenitor cells from the transplanted graft may generate endothelial cells in an appropriate host environment [72]; [3] Numerous cytokines secreted by HSCs/HPCs and transplanted niche cells may influence the microenvironment and enhance BM stem cell homing and subsequent hematopoiesis [69, 71, 73]
Summary
Acquired aplastic anemia (AA) is characterized by a hypoplastic, fatty bone marrow (BM) with profound reductions in hematopoietic stem/progenitor cells (HSCs/HPCs) that lead to defective mature blood cell production and peripheral pancytopenia [1,2,3]. Given the deficit in HSCs/HPCs observed in patients with acquired AA or BMF, replacing these by allogeneic hematopoietic cell transplantation (allo-HCT) is an obvious treatment option [8,9,10] (Figure 1).
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