Project 3 Abstract Metabolic regulation of human erythropoiesis The self renewal capacity of hematopoietic stem cells (HSCs) is controlled by the cells' metabolic state but the possibility that nutrient entry and metabolism contribute to the differential commitment of an HSC to a lymphoid, myeloid or erythroid lineage fate was not considered until very recently. The overall goal of this project is to develop a mechanistic understanding of the role of cell metabolism in physiological and disordered erythropoiesis. Our studies address the hypothesis that nutrient transport and utilization regulate both normal and pathological human erythroid differentiation. Our previous data show that the glucose transporter Glut1 is only upregulated during the final mitoses of human erythroid differentiation (Montel- Hagen et al. Cell 2008) whereas the glutamine transporter ASCT2 is expressed on all HSCs. We determined that down regulation of ASCT2 or blocking glutamine metabolism abrogates erythroid differentiation and skews erythropoietin-treated HSCs towards a myeloid fate. In contrast, diverting glucose into the pentose phosphate pathway, away from glycolysis, accelerates erythropoiesis (Oburoglu et al. Cell Stem Cell 2014).
In Aim 1, we will use our unique collection of retroviral envelope receptor binding domains (RBDs), that function as specific ligands of solute carrier (SLC) nutrient transporters, to characterize stage- specific expression and function of transporters and determine the array of transporters regulating erythropoiesis in normal conditions as well as in erythroid progenitors with altered nuclear lamins (with Project 4), in a TET2-deficient model of myelodysplastic syndrome, and in RPL5- and RPL11-deficient models of Diamond Blackfan anemia (with Project 1).
In Aim 2, we will assess metabolic fluxes from stable glucose, glutamine, and fatty acid isotope tracers, elucidating the metabolic networks and metabolites that regulate normal and perturbed erythropoiesis. These studies will critically address our hypothesis that fuel resource utilization governs early and terminal erythroid differentiation, at a level beyond simply providing the ATP, amino acids and lipids that are required for cell division. We propose that metabolic changes contribute to stage-specific epigenetic, transcriptional and translational erythroid regulatory programs which will be evaluated with Project 2. We anticipate that integration of these data within the Program Project will identify the nutrient fluxes and utilization that control stage-specific erythroid transitions, pioneer nutrient transporter biomarker discovery in erythroid disorders, and promote the manipulation of nutrient transporters and metabolic networks that orient physiological and pathological erythroid cell differentiation and survival.
Project 3: NARRATIVE Stem cells have the capacity to generate all blood lineages and the development of red blood cells is critical for survival. While we have gained significant insights into the importance of proteins such as erythropoietin in red cell development, our mechanistic understanding of how nutrient entry and metabolism regulate erythropoiesis is much less clear. Here, we will explore our hypothesis that nutrient transport and utilization differentially regulate human red cell development in healthy individuals as compared to patients with disordered erythropoiesis. We anticipate that our findings will provide novel insights into erythroid cell development and may allow us to envisage novel therapeutic strategies for patients with anemia. 22
|Qu, Xiaoli; Zhang, Shijie; Wang, Shihui et al. (2018) TET2 deficiency leads to stem cell factor-dependent clonal expansion of dysfunctional erythroid progenitors. Blood 132:2406-2417|
|Huang, Yumin; Hale, John; Wang, Yaomei et al. (2018) SF3B1 deficiency impairs human erythropoiesis via activation of p53 pathway: implications for understanding of ineffective erythropoiesis in MDS. J Hematol Oncol 11:19|
|Ali, Abdullah Mahmood; Huang, Yumin; Pinheiro, Ronald Feitosa et al. (2018) Severely impaired terminal erythroid differentiation as an independent prognostic marker in myelodysplastic syndromes. Blood Adv 2:1393-1402|
|Yan, Hongxia; Hale, John; Jaffray, Julie et al. (2018) Developmental differences between neonatal and adult human erythropoiesis. Am J Hematol 93:494-503|
|Han, Xu; Zhang, Jieying; Peng, Yuanliang et al. (2017) Unexpected role for p19INK4d in posttranscriptional regulation of GATA1 and modulation of human terminal erythropoiesis. Blood 129:226-237|
|Gastou, Marc; Rio, Sarah; Dussiot, Michaël et al. (2017) The severe phenotype of Diamond-Blackfan anemia is modulated by heat shock protein 70. Blood Adv 1:1959-1976|
|Irianto, Jerome; Pfeifer, Charlotte R; Xia, Yuntao et al. (2016) SnapShot: Mechanosensing Matrix. Cell 165:1820-1820.e1|
|Pimentel, Harold; Parra, Marilyn; Gee, Sherry L et al. (2016) A dynamic intron retention program enriched in RNA processing genes regulates gene expression during terminal erythropoiesis. Nucleic Acids Res 44:838-51|
|Sosale, Nisha G; Spinler, Kyle R; Alvey, Cory et al. (2015) Macrophage engulfment of a cell or nanoparticle is regulated by unavoidable opsonization, a species-specific 'Marker of Self' CD47, and target physical properties. Curr Opin Immunol 35:107-12|
|Ivanovska, Irena L; Shin, Jae-Won; Swift, Joe et al. (2015) Stem cell mechanobiology: diverse lessons from bone marrow. Trends Cell Biol 25:523-32|
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