REGULATION OF STRESS ERYTHROPOIESIS AND THE NICHE: A NOVAL ROLE OF SELENOPROTEINS
Open Access
- Author:
- Liao, Chang
- Graduate Program:
- Pathobiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- September 10, 2018
- Committee Members:
- K. Sandeep Prabhu, Dissertation Advisor/Co-Advisor
K. Sandeep Prabhu, Committee Chair/Co-Chair
Robert Paulson, Committee Member
Pamela Hankey Giblin, Committee Member
Qunhua Lia, Outside Member - Keywords:
- Selenoproteins
Stress erythropoiesis
Erythropoietic nice - Abstract:
- Selenium (Se) is incorporated as the 21st amino acid selenocysteine (Sec) into the growing polypeptide chain of proteins involved in redox gatekeeper functions. Twenty five selenoprotein genes have been discovered in human (twenty four in rodents) that partake a key role in redox homeostasis. Other physiological functions include mediating thyroid hormone production, benefiting cardiovascular health, and broader anti-inflammatory activities. Insufficiency of Se and selenoproteins contributes to many pathophysiological conditions, including cardiomyopathy (Keshan disease), arthritis (Kashin-Beck disease) and defects in the immune response to viral infection. The beneficial biochemical role of Se in erythrocytes was first defined in 1973 in the form of selenoenzyme glutathione peroxidases that highlighted the important role of dietary Se, which contributed, in part, to cellular stabilization. Erythropoiesis presents a particular problem to redox regulation as the presence of iron, heme, and unpaired globin chains lead to high levels of free radical-mediated oxidative stress, which are detrimental to erythroid development and can lead to anemia. In the recent years, Se deficiency has been linked to anemia associated with aging and chronic inflammatory diseases in humans. Studies suggest that dietary Se protects erythrocytes from such oxidative damage, and the absence of selenoproteins causes hemolysis of erythrocytes due to oxidative stress. Furthermore, Se deficiency or lack of selenoproteins severely impairs stress erythropoiesis exacerbating the anemia in rodent models and human patients. In addition, erythroid progenitors develop in close proximity with macrophages in structures referred to as erythroblastic islands (EBIs), where macrophage expression of selenoproteins appears to be critical for the expression of heme transporters to facilitate export of heme from macrophage stores to the developing erythroid cells. Se and selenoproteins have emerged to be crucial and beneficial to erythroid cells and erythropoiesis, where they are intricately involved in multiple ways. In this dissertation, the role of Se and selenoproteins in the intrinsic development of erythroid cells will be discussed, in addition to their role in the development of the erythropoietic niche that supports the functional role of EBIs in erythroid expansion and maturation in the spleen during the recovery from anemia. Chapter 2 covers the discussion of phenotypes and mechanisms of selenoproteins in regulation of stress erythropoiesis. Loss of selenoproteins through Se deficiency or by mutation of the Sec tRNA (tRNA [Sec] or Trsp) gene severely impairs stress erythropoiesis. Se deficiency or mutation of Trsp causes defects at two stages of stress erythropoiesis. The loss of selenoproteins results in a failure to expand early stress erythroid progenitors and stress burst forming unit-erythroids (BFU-Es) in the spleen. Furthermore, late stage erythroid progenitors exhibit a maturation defect that affects the transition of proerythroblasts to basophilic erythroblasts. This defect is associated with augmented cleavage of the transcription factor GATA-1. Transcriptomic analysis reveals significant differences in gene expression in proerythroblasts as a function of Se status. In particular, the expression of selenoprotein W (SelenoW) is decreased in Se deficient cells suggesting its role in stress erythropoiesis. Mutation of SelenoW in mouse and human bone marrow significantly decreases the expansion of stress BFU-Es, which recapitulates the defect in stress erythropoiesis induced by Se deficiency or mutation of Trsp. Similarly, mutation of SelenoW in a murine erythroblastic cell line, G1E cells, leads to defects in terminal differentiation. In addition to the erythroid defects, the spleens of Se deficient mice have significantly fewer red pulp macrophages that form the erythropoietic niche, which demonstrates a role for selenoproteins in development of the stress erythropoiesis niche in the spleen. The study reveals a critical role of selenoproteins in the expansion and development of stress erythroid progenitors as well as the erythroid niche during acute anemia recovery. Chapter 3 discusses the properties and regulation of the stress erythropoietic niche in the perspective of normal physiological conditions, aiming to broaden the current understanding of stress erythropoiesis. Erythropoietic functions of macrophages have been recognized for maintaining erythroid homeostasis by forming erythropoietic niches for supporting erythroblast maturation. The heterogeneity of macrophages has been intensively studied however it is less known about the composition of niche center cells. Two models are used, including short-term radio protection post bone marrow transplantation mouse model and phenylhydrazine induced acute anemia mouse model, to characterize that the stress erythropoietic niche in the spleen is highly dynamic and heterogeneous consisted of multiple subsets of monocytes and macrophages, in which monocytes serve multiple roles in supporting stress recovery. Notably, erythrophagocytosis is an initiator of recovery events in response to irradiation stress, that occurs exclusively during early recovery, which can induce monocytes differentiation into red pulp macrophages. Furthermore, erythrophagocytotic cells are chemoattractant Ccl2 producers, that recruits monocytes into the stress niche to replenish macrophage pool and support expansion of stress erythroid progenitors. Ccl2 can be induced by aged red blood cells or interferon-gamma that is produced by monocytes in response to stress. The study establishes a dynamic model for erythropoietic niche monocytes and macrophages during stress erythropoiesis, where erythrophagocytosis and monocytes uniquely contribute at multiple levels.