Macrophage depletion following liposomal‐encapsulated clodronate (LIP‐CLOD) injection enhances megakaryocytopoietic and thrombopoietic activities in mice

Abstract

Summary. Megakaryocytopoiesis is the cellular process by which stem cells progress through commitment, proliferation and differentiation, leading to the production of platelets. In the mouse, this process is accomplished within the bone marrow (BM) and spleen microenvironment and is carried out by regulatory molecules and accessory cells, including macrophages, fibroblasts and endothelial‐like cells. Previously, we demonstrated that specific macrophage depletion, using liposomal‐encapsulated clodronate (LIP‐CLOD), induced a rapid recovery of the platelet count in a mouse model of immune thrombocytopenia. We now show that LIP‐CLOD treatment also provoked enhancement of both megakaryocytopoiesis and thrombocytopoiesis. In fact, a dose‐dependent increase in the number of BM and spleen megakaryocytes was detected after treatment and this pattern correlated inversely to the macrophage count detected in these organs. Furthermore, the mice treated with the higher dose of LIP‐CLOD showed signs of enhanced thrombopoiesis as they had an increased frequency of reticulated platelets and an improvement in the total platelet count 2 d later. In addition, the in vitro cytokine‐induced megakaryocytopoiesis in BM and spleen cell cultures was significantly augmented in the presence of LIP‐CLOD. Taken together, these results suggest that BM and spleen microenvironmental macrophages could be involved in the regulation of megakaryocyte and platelet production.

Hematopoietic stem cell loss and hematopoietic failure in severe aplastic anemia is driven by macrophages and aberrant podoplanin expression

“…Our findings are consistent with and add to previous reports of Mϕ−dependent impairment of megakaryopoiesis and platelet production at steady state. 46,47 Additionally, macrophage-colony stimulating factor M-CSF, a factor that increases Mϕ self-renewal, transiently causes thrombocytopenia. 47 Our study builds upon these findings and identify Mϕs as key sensors or target cells of IFNγ.…”

Secondary Intracerebral Hemorrhage Due to Early Initiation of Oral Anticoagulation After Ischemic Stroke

“…21 Of note, clodronate liposomes do not deplete platelets but rather increase thrombopoietic activities, excluding that the observed bleedings are caused by a loss of platelets. 22 In our previous study in nonanticoagulated mice, infarct hemorrhage after extensive macrophage depletion occurred between days 2 and 3 after stroke onset, 17 corresponding to the temporal risk profile delineated in our present study. This suggested that macrophage-dependent brain repair may be involved in the prevention of OAC-associated sICH.…”

Development and function of the mammalian spleen

“…(80) This is the result of no sequestering or destruction of platelets by the spleen, as well as a slight increase in platelet production in the bone marrow, (81) the latter possibly because splenic macrophages and other spleen stromal cell populations are involved in the regulation of platelet production. (82) Serious thromboembolic events can accompany splenectomy (pulmonary embolism, deep vein and portal vein thrombosis) and may be related to a procoagulant activity of substances released from circulating damaged erythrocytes.…”