Transferrin receptor 1-mediated iron uptake plays an essential role in hematopoiesis

Wang, Shufen; He, Xuyan; Wu, Qian; Jiang, Li; Chen, Liyun; Yu, Yingying; Zhang, Pan; Huang, Xin; Wang, Jia; Ju, Zhenyu; Min, Junxia; Wang, Fudi

doi:10.3324/haematol.2019.224899

Cited by 65 publications

(35 citation statements)

References 51 publications

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“…To examine the role of hepatic Trf in the development of proerythroblasts into mature red blood cells, flow cytometry was performed by using the erythroid lineage markers Ter119 and CD44. 27 We found that the cell number of polychromatophilic erythroblasts (R3) increased significantly, whereas orthochromatophilic erythroblasts (R4) and mature erythrocytes (R5) were significantly decreased in the bone marrow of Trf-LKO mice compared with control mice (supplemental Figure 2C). The reticulocyte count decreased in the bone marrow and increased in the circulation, which is consistent with normal compensatory responses to release reticulocytes into the circulation earlier in conditions of more severe anemia.…”

Section: Trf-lko Mice Have Impaired Erythropoiesis and Altered Iron Mmentioning

confidence: 80%

Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis

Jiang

Wang

et al. 2020

Blood

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363

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Although the serum-abundant metal-binding protein transferrin (encoded by the Trf gene) is synthesized primarily in the liver, its function in the liver is largely unknown. Here, we generated hepatocyte-specific Trf knockout mice (Trf-LKO), which are viable and fertile but have impaired erythropoiesis and altered iron metabolism. Moreover, feeding Trf-LKO mice a high-iron diet increased their susceptibility to develop ferroptosis-induced liver fibrosis. Importantly, we found that treating Trf-LKO mice with the ferroptosis inhibitor ferrostatin-1 potently rescued liver fibrosis induced by either high dietary iron or carbon tetrachloride (CCl4) injections. In addition, deleting hepatic Slc39a14 expression in Trf-LKO mice significantly reduced hepatic iron accumulation, thereby reducing ferroptosis-mediated liver fibrosis induced by either high dietary iron diet or CCl4 injections. Finally, we found that patients with liver cirrhosis have significantly lower levels of serum transferrin and hepatic transferrin, as well as higher levels of hepatic iron and lipid peroxidation compared to healthy controls. Taken together, these data indicate that hepatic transferrin plays a protective role in maintaining liver function, providing a possible therapeutic target for preventing ferroptosis-induced liver fibrosis.

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Section: Trf-lko Mice Have Impaired Erythropoiesis and Altered Iron Mmentioning

confidence: 80%

Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis

Jiang

Wang

et al. 2020

Blood

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363

240

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“…Multiple studies have shown that Tfr1 deficiency results in functional disorder and even lethality. Mice with Tfr1 conditional knockout in haematopoietic stem cells died within 1 week after birth 23 . Our previous study demonstrated that Tfr1 regulates adipocyte thermogenesis and cell fate determination 13 .…”

Section: Discussionmentioning

confidence: 99%

Transferrin receptor 1 ablation in satellite cells impedes skeletal muscle regeneration through activation of ferroptosis

Ding

Chen

Pan

et al. 2021

J cachexia sarcopenia muscle

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Background Satellite cells (SCs) are critical to skeletal muscle regeneration. Inactivation of SCs is linked to skeletal muscle loss. Transferrin receptor 1 (Tfr1) is associated with muscular dysfunction as muscle‐specific deletion of Tfr1 results in growth retardation, metabolic disorder, and lethality, shedding light on the importance of Tfr1 in muscle physiology. However, its physiological function regarding skeletal muscle ageing and regeneration remains unexplored. Methods RNA sequencing is applied to skeletal muscles of different ages to identify Tfr1 associated to skeletal muscle ageing. Mice with conditional SC ablation of Tfr1 were generated. Between Tfr1SC/WT and Tfr1SC/KO (n = 6–8 mice per group), cardiotoxin was intramuscularly injected, and transverse abdominal muscle was dissected, weighted, and cryosectioned, followed by immunostaining, haematoxylin and eosin staining, and Masson staining. These phenotypical analyses were followed with functional analysis such as flow cytometry, tread mill, Prussian blue staining, and transmission electron microscopy to identify pathological pathways that contribute to regeneration defects. Results By comparing gene expression between young (2 weeks old, n = 3) and aged (80 weeks old, n = 3) mice among four types of muscles, we identified that Tfr1 expression is declined in muscles of aged mice (~80% reduction, P < 0.005), so as to its protein level in SCs of aged mice. From in vivo and ex vivo experiments, Tfr1 deletion in SCs results in an irreversible depletion of SCs (~60% reduction, P < 0.005) and cell‐autonomous defect in SC proliferation and differentiation, leading to skeletal muscle regeneration impairment, followed by labile iron accumulation, lipogenesis, and decreased Gpx4 and Nrf2 protein levels leading to reactive oxygen species scavenger defects. These abnormal phenomena including iron accumulation, activation of unsaturated fatty acid biosynthesis, and lipid peroxidation are orchestrated with the occurrence of ferroptosis in skeletal muscle. Ferroptosis further exacerbates SC proliferation and skeletal muscle regeneration. Ferrostatin‐1, a ferroptosis inhibitor, could not rescue ferroptosis. However, intramuscular administration of lentivirus‐expressing Tfr1 could partially reduce labile iron accumulation, decrease lipogenesis, and promote skeletal muscle regeneration. Most importantly, declined Tfr1 but increased Slc39a14 protein level on cellular membrane contributes to labile iron accumulation in skeletal muscle of aged rodents (~80 weeks old), leading to activation of ferroptosis in aged skeletal muscle. This is inhibited by ferrostatin‐1 to improve running time (P = 0.0257) and distance (P = 0.0248). Conclusions Satellite cell‐specific deletion of Tfr1 impairs skeletal muscle regeneration with activation of ferroptosis. This phenomenon is recapitulated in skeletal muscle of aged rodents and human sarcopenia. Our study provides mechanistic information for developing novel therapeutic strategies against muscular ageing and diseases.

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“…Iron is crucial for normal hematopoiesis since TFR1 inhibition and subsequent iron depletion impair the proliferation and differentiation of hematopoietic precursor cells, and reduce the regeneration potential of hematopoietic stem cells (HSCs) (20). Notably however, excess iron and ROS catalytic production also promote the malignant transformation of HSCs through nicotinamide adenine dinucleotide phosphate oxidases (NOX) and the subsequent depletion of glutathione (GSH) (21).…”

Section: Iron and Acute Myeloid Leukemiamentioning

confidence: 99%

From Iron Chelation to Overload as a Therapeutic Strategy to Induce Ferroptosis in Leukemic Cells

et al. 2020

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Despite its crucial importance in numerous physiological processes, iron also causes oxidative stress and damage which can promote the growth and proliferation of leukemic cells. Iron metabolism is strictly regulated and the related therapeutic approaches to date have been to restrict iron availability to tumor cells. However, since a new form of ironcatalyzed cell death has been described, termed ferroptosis, and subsequently better understood, iron excess is thought to represent an opportunity to selectively kill leukemic cells and spare normal hematopoietic cells, based on their differential iron needs. This review summarizes the physiology of iron metabolism and its deregulation in leukemia, the known ferrotoposis pathways, and therapeutic strategies to target the altered iron metabolism in leukemia for the purposes of initiating ferroptosis in these cancer cells.

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Transferrin receptor 1-mediated iron uptake plays an essential role in hematopoiesis

Cited by 65 publications

References 51 publications

Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis

Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis

Transferrin receptor 1 ablation in satellite cells impedes skeletal muscle regeneration through activation of ferroptosis

From Iron Chelation to Overload as a Therapeutic Strategy to Induce Ferroptosis in Leukemic Cells

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