Modest Declines in Proteome Quality Impair Hematopoietic Stem Cell Self-Renewal.

Last updated: 05-09-2020

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Modest Declines in Proteome Quality Impair Hematopoietic Stem Cell Self-Renewal.

Low protein synthesis is a feature of somatic stem cells that promotes regeneration in multiple tissues. Modest increases in protein synthesis impair stem cell function, but the mechanisms by which this occurs are largely unknown. We determine that low protein synthesis within hematopoietic stem cells (HSCs) is associated with elevated proteome quality in vivo. HSCs contain less misfolded and unfolded proteins than myeloid progenitors. Increases in protein synthesis cause HSCs to accumulate misfolded and unfolded proteins. To test how proteome quality affects HSCs, we examine Aars mice that harbor a tRNA editing defect that increases amino acid misincorporation. Aars mice exhibit reduced HSC numbers, increased proliferation, and diminished serial reconstituting activity. Misfolded proteins overwhelm the proteasome within Aars HSCs, which is associated with increased c-Myc abundance. Deletion of one Myc allele partially rescues serial reconstitution defects in Aars HSCs. Thus, HSCs are dependent on low protein synthesis to maintain proteostasis, which promotes their self-renewal.

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The release of stem cells from the bone marrow into the peripheral blood circulation for the purpose of leukapheresis, prior to stem cell transplantation. Hematopoietic growth factors or chemotherapeutic agents often are used to stimulate the mobilization. Transfer of HEMATOPOIETIC STEM CELLS from BONE MARROW or BLOOD between individuals within the same species (TRANSPLANTATION, HOMOLOGOUS) or transfer within the same individual (TRANSPLANTATION, AUTOLOGOUS). Hematopoietic stem cell transplantation has been used as an alternative to BONE MARROW TRANSPLANTATION in the treatment of a variety of neoplasms. A hematopoietic growth factor and the ligand of the cell surface c-kit protein (PROTO-ONCOGENE PROTEINS C-KIT). It is expressed during embryogenesis and is a growth factor for a number of cell types including the MAST CELLS and the MELANOCYTES in addition to the HEMATOPOIETIC STEM CELLS. Clonal hematopoietic stem cell disorders characterized by dysplasia in one or more hematopoietic cell lineages. They predominantly affect patients over 60, are considered preleukemic conditions, and have high probability of transformation into ACUTE MYELOID LEUKEMIA. Bipotential angio-hematopoietic stem cells that give rise to both HEMATOPOIETIC STEM CELLS and ENDOTHELIAL CELLS.

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