Glucose Metabolism and Aging of Hematopoietic Stem and Progenitor Cells

Abstract

Comprehensive proteomics studies of human hematopoietic stem and progenitor cells (HSPC) have revealed that aging of the HSPC compartment is characterized by elevated glycolysis. This is in addition to deregulations found in murine transcriptomics studies, such as an increased differentiation bias towards the myeloid lineage, alterations in DNA repair, and a decrease in lymphoid development. The increase in glycolytic enzyme activity is caused by the expansion of a more glycolytic HSPC subset. We therefore developed a method to isolate HSPC into three distinct categories according to their glucose uptake (GU) levels, namely the GUhigh, GUinter and GUlow subsets. Single-cell transcriptomics studies showed that the GUhigh subset is highly enriched for HSPC with a differentiation bias towards myeloid lineages. Gene set enrichment analysis (GSEA) demonstrated that the gene sets for cell cycle arrest, senescence-associated secretory phenotype, and the anti-apoptosis and P53 pathways are significantly upregulated in the GUhigh population. With this series of studies, we have produced a comprehensive proteomics and single-cell transcriptomics atlas of molecular changes in human HSPC upon aging. Although many of the molecular deregulations are similar to those found in mice, there are significant differences. The most unique finding is the association of elevated central carbon metabolism with senescence. Due to the lack of specific markers, the isolation and collection of senescent cells have yet to be developed, especially for human HSPC. The GUhigh subset from the human HSPC compartment possesses all the transcriptome characteristics of senescence. This property may be exploited to accurately enrich, visualize, and trace senescence development in human bone marrow.

Cerebral Microvascular Senescence and Inflammation in Diabetes

“…Senescence can also lead to cellular metabolic changes with deleterious consequences. For example, human hematopoietic stem and progenitor cells as well as human fibroblasts have been shown to display increased glucose uptake and glycolysis, and lipid accumulation (Gorgoulis et al, 2019;Poisa-Beiro et al, 2022). This alteration in lipid handling is detrimental in that it accumulates within lysosomes as indigestible lipofuscin, impairing lysosomal function and autophagic capabilities.…”

Lysosomes and Their Role in Regulating the Metabolism of Hematopoietic Stem Cells

“…Several glycolytic enzymes are upregulated in aging HSPCs [ 189 ], possibly contributing to CHIP formation. CHIP therapy focuses on preventing the onset and progression of hematological malignancies.…”

Inhibitory effort of MLN2238 on basal-like breast cancer: An investigation based on the gene set enrichment analysis

“…The research showed that the structure of MLN2238 is different from bortezomib (15). MLN2238 (ixazomib) has been given great promise because of the proven clinical effects of bortezomib which was another proteasome inhibitor (16,17). Moreover, the disassociation half-life of ixazomib was six-fold faster than bortezomib which made ixazomib fast dissociate from red blood cells and rapidly entered into the tumor cells (18).…”