Use of dual electron probes reveals role of ferritin in erythropoiesis

Abstract

Much is known about the finely regulated process of mammalian erythropoiesis that occurs in the bone marrow, whereby erythropoietic stem cells undergo terminal differentiation accompanied by enormous morphological changes to generate highly functional specialized red blood cells. However, a crucial step in erythropoiesis, the labile iron pool and its transport to mitochondria for heme production, is not well understood1. We apply a dual 3D imaging and spectroscopic technique, based on scanned electron probes, to measure distributions of ferritin iron-storage protein in ex vivo human erythropoietic stem cells, and to determine how those distributions change during terminal differentiation. After seven days of differentiation, the cells display a highly specialized architecture of organelles with anchored clustering of mitochondria and massive accumulation of Fe3+ in loaded ferritin cores localized to lysosomal storage depots, providing an iron source for heme production. Macrophages are not present in our ex vivo cultures, so they cannot be the source of the ferritin2. We suggest that lysosomal iron depots are required by developing reticulocytes while terminally differentiating and continuing to produce heme and globin, which assemble and concentrate to fill the cytoplasm after much of the cellular machinery is expelled.