Publications by authors named "Ira Phadke"

Hematopoietic stem cells (HSCs) possess the capacity for self-renewal and the sustained production of all mature blood cell lineages. It has been well established that a metabolic rewiring controls the switch of HSCs from a self-renewal state to a more differentiated state, but it is only recently that we have appreciated the importance of metabolic pathways in regulating the commitment of progenitors to distinct hematopoietic lineages. In the context of erythroid differentiation, an extensive network of metabolites, including amino acids, sugars, nucleotides, fatty acids, vitamins, and iron, is required for red blood cell (RBC) maturation.

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Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate, but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. Here, we show that SLC7A1/cationic amino acid transporter 1-dependent arginine uptake and its catabolism to the polyamine spermidine control human erythroid specification of HSPCs via the activation of the eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on its hypusination, a posttranslational modification resulting from the conjugation of the aminobutyl moiety of spermidine to lysine.

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Hematopoiesis, a process that results in the differentiation of all blood lineages, is essential throughout life. The production of 1x10 blood cells per day, including 200x10 erythrocytes, is highly dependent on nutrient consumption. Notably though, the relative requirements for micronutrients during the perinatal period, a critical developmental window for immune cell and erythrocyte differentiation, have not been extensively studied.

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Fibrosis, the pathological end stage of chronic inflammatory diseases, results from extracellular matrix deposition by fibrogenic fibroblasts. In this issue of Cell Stem Cell, Sobecki et al. (2022) develop a novel vaccination-based immunotherapy against fibrogenic progenitor-restricted antigens, leading to the regression of fibrosis in concert with liver and lung regeneration.

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Article Synopsis
  • - Non-alcoholic steatohepatitis (NASH) is rapidly becoming a leading cause of liver cancer (hepatocellular carcinoma, HCC) and may reduce the effectiveness of immune checkpoint inhibitors (ICI) used for treatment.
  • - Research using mouse models showed that NASH disrupts CD8 T cells' metabolism and mobility, diminishing their response to anti-PD-1 therapy against liver cancer.
  • - Metformin treatment was found to improve the efficacy of anti-PD-1 therapy in liver cancer associated with NASH, indicating potential therapeutic benefits for patients with this condition.
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The metabolic changes controlling the stepwise differentiation of hematopoietic stem and progenitor cells (HSPCs) to mature erythrocytes are poorly understood. Here, we show that HSPC development to an erythroid-committed proerythroblast results in augmented glutaminolysis, generating alpha-ketoglutarate (αKG) and driving mitochondrial oxidative phosphorylation (OXPHOS). However, sequential late-stage erythropoiesis is dependent on decreasing αKG-driven OXPHOS, and we find that isocitrate dehydrogenase 1 (IDH1) plays a central role in this process.

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