Complex Interactions in Regulation of Haematopoiesis-An Unexplored Iron Mine

Abstract

Iron is one of the most abundant metals on earth and is vital for the growth and survival of life forms. It is crucial for the functioning of plants and animals as it is an integral component of the photosynthetic apparatus and innumerable proteins and enzymes. It plays a pivotal role in haematopoiesis and affects the development and differentiation of different haematopoietic lineages, apart from its obvious necessity in erythropoiesis. A large amount of iron stores in humans is diverted towards the latter process, as iron is an indispensable component of haemoglobin. This review summarises the important players of iron metabolism and homeostasis that have been discovered in recent years and highlights the overall significance of iron in haematopoiesis. Its role in maintenance of haematopoietic stem cells, influence on differentiation of varied haematopoietic lineages and consequences of iron deficiency/overloading on development and maturation of different groups of haematopoietic cells have been discussed.

Keywords: haematopoietic lineages; haematopoietic stem cells; homeostasis; iron; iron deficiency and overloading.

Figure 1

Dietary iron is principally absorbed by enterocytes of the duodenum by the divalent metal transporter 1 (DMT1) in the ferrous (Fe²⁺) state after being reduced from ferric (Fe³⁺) state by the duodenal cytochrome B (DCYTB). While transferrin-bound iron is taken up by the transferrin receptor (TfR1), non-transferrin-bound iron (NTBI) was recently discovered to be taken up by the ZRT/IRT like protein members (ZIP 8,14) in association with the ferrireductase prion protein (PRNP). Transferrin-bound iron is internalised into acidic endosomes by ‘endocytosis’, released from TfR1 and reduced to Fe²⁺ state by the epithelial antigen of prostate 3 (STEAP3). Fe²⁺ iron is released from endosomes into the cytoplasm by DMT1 and ZIP 8/14. The cytosolic labile iron pool (LIP) composed of Fe²⁺ may be delivered to the iron exporter ferroportin (FPN) by members of iron chaperones i.e., poly-(rC)-binding proteins (PCBPs). Iron is finally exported out of the cell into the circulatory system via the copper-dependent ferroxidase hephaestin (HEPH). PCBP 1 and 2 may also transport Fe²⁺ to ferritin, where it is oxidised to Fe³⁺ and stored in an intracellular non-toxic form. Iron-loaded ferritin may also undergo degradation by autophagy with the aid of the nuclear receptor coactivator 4 (NCOA4), which releases iron for cellular use, such as in synthesis of heme or iron sulphur cluster (Fe-S) formation.