(A) Basic model of myelofibrosis. Increased vitamin D (VitD) signaling resulting from high circulating 1,25(OH)₂ vitamin D₃ levels acting on transplanted VDR^+/+ hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) facilitates bone marrow macrophage differentiation. Bone marrow macrophages are proposed to be critical mediators of the development of bone marrow fibrosis acting in concert with other cells observed in fibrotic areas such as osterix⁺ α-smooth muscle actin–positive (osterix⁺αSMA⁺) myofibroblasts and osteoblasts and potentially downstream of megakaryocytes, which were not observed in regions of fibrosis. (B) Mitigation of myelofibrosis in the basic and JAK2V617F transplantation models of myelofibrosis. Reducing VitD signaling by reducing circulating 1,25(OH)₂ vitamin D₃ levels using a diet low in vitamin D or genetic deletion of the VitD receptor (blue panel) or direct depletion of macrophages (green panel) prevents the development of myelofibrosis in the basic model and a JAK2V617F transplantation model of myelofibrosis. Professional illustration by Somersault18:24. This figure is based on Figure 5C in the article by Wakahashi that begins on page 1619.