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Iron Metabolism & its Disorders
Transferrin receptor 1-mediated iron uptake plays an essential role in hematopoiesis
Ferrata Storti Foundation
Haematologica 2020 Volume 105(8):2071-2082
Shufen Wang,1,2* Xuyan He,1* Qian Wu,1 Li Jiang,1 Liyun Chen,1 Yingying Yu,1 Pan Zhang,1 Xin Huang,3 Jia Wang,3 Zhenyu Ju,4 Junxia Min1 and Fudi Wang1,2,3
1The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhenjiang Provincial Key Laboratory of Pancreatic Disease, Zhejiang University School of Medicine, Hangzhou; 2Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing; 3Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, Zhengzhou and 4Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China
#SW and XH contributed equally as co-first authors.
ABSTRACT
Transferrin receptor 1 (Tfr1) mediates the endocytosis of diferric trans- ferrin in order to transport iron, and Tfr1 has been suggested to play an important role in hematopoiesis. To study the role of Tfr1 in hematopoiesis, we generated hematopoietic stem cell (HSC) specific Tfr1 knockout mice. We found that Tfr1 conditional knockout mice reached full term but died within one week of birth. Further analyses revealed that Tfr1- deficient HSC had impaired development of all hematopoietic progenitors except thrombocytes and B lymphocytes. In addition, Tfr1-deficient cells had cellular iron deficiency, which blocked the proliferation and differentia- tion of hematopoietic precursor cells, attenuated the commitment of hematopoietic lineages, and reduced the regeneration potential of HSC. Notably, hemin rescued the colony-forming capacity of Tfr1-deficient HSC, whereas expressing a mutant Tfr1 that lacks the protein’s iron-transporting capacity failed to rescue hematopoiesis. These findings provide direct evi- dence that Tfr1 is essential for hematopoiesis through binding diferric trans- ferrin to supply iron to cells.
Introduction
Hematopoietic stem cells (HSC) are essential for the continuous replenishment of the hematopoietic system throughout the lifespan of an organism.1-4 HSC regulate development 5,6 and undergo important changes during aging.7 However, precisely how HSC orchestrate the delicate balance between proliferation, differentiation, and self-renewal remains one of the major topics of study in the field of stem cell biology.
Iron is essential for a variety of fundamental metabolic processes and is incorpo- rated into many proteins in the form of cofactors such as heme and iron-sulfur clus- ters. In adults, a substantial proportion of iron is present in the liver and the hematopoietic system. Excess iron in the liver is clinically relevant, as individuals with systemic iron overload often develop liver cirrhosis and hepatocellular carci- noma.8 On the other hand, hematopoiesis is sensitive to iron deficiency, and insuf- ficient iron leads to iron deficiency anemia.9 Although iron serves as an essential cofactor for enzymes involved in cell proliferation and differentiation, the precise mechanism that regulates iron homeostasis in HSC is unknown.
Transferrin receptor 1 (Tfr1) facilitates the uptake of iron at the cell surface by internalizing diferric transferrin.10 Tfr1 is ubiquitously expressed in mammalian tis- sues and has been called the “cellular iron gate”.11 Tfr1 is essential for erythro- poiesis, a process that consumes the majority of circulating iron.12 Accordingly, mice that globally lack Tfr1 (i.e. homozygous Tfr1 knockout mice) are embryonic lethal; moreover, although heterozygous Tfr1 knockout mice survive to adulthood they have microcytic hypochromic erythrocytes, consistent with Tfr1’s essential role in erythropoiesis.13 In addition, Tfr1 plays an important role in the develop-
Correspondence:
FUDI WANG
fwang@zju.edu.cn
JUNXIA MIN
junxiamin@zju.edu.cn
Received: April 17, 2019. Accepted: October 4, 2019. Pre-published: October 10, 2019.
doi:10.3324/haematol.2019.224899
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/8/2071
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