Mariana Borsa, Sandrine Obba, Felix C Richter, Hanlin Zhang, Thomas Riffelmacher, Joana Carrelha, Ghada Alsaleh, Sten Eirik W Jacobsen, Anna Katharina Simon
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引用次数: 0
Abstract
Adult stem cells are long-lived and quiescent with unique metabolic requirements. Macroautophagy/autophagy is a fundamental survival mechanism that allows cells to adapt to metabolic changes by degrading and recycling intracellular components. Here we address why autophagy depletion leads to a drastic loss of the stem cell compartment. Using inducible deletion of autophagy specifically in adult hematopoietic stem cells (HSCs) and in mice chimeric for autophagy-deficient and normal HSCs, we demonstrate that the stem cell loss is cell-intrinsic. Mechanistically, autophagy-deficient HSCs showed higher expression of several amino acid transporters (AAT) when compared to autophagy-competent cells, resulting in increased amino acid (AA) uptake. This was followed by sustained MTOR (mechanistic target of rapamycin) activation, with enlarged cell size, glucose uptake and translation, which is detrimental to the quiescent HSCs. MTOR inhibition by rapamycin treatment in vivo was able to rescue autophagy-deficient HSC loss and bone marrow failure and resulted in better reconstitution after transplantation. Our results suggest that targeting MTOR may improve aged stem cell function, promote reprogramming and stem cell transplantation.List of abbreviations: 5FU: fluoracil; AA: amino acids; AKT/PKB: thymoma viral proto-oncogene 1; ATF4: activating transcription factor 4; BafA: bafilomycin A1; BM: bone marrow; EIF2: eukaryotic initiation factor 2; EIF4EBP1/4EBP1: eukaryotic translation initiation factor 4E binding protein 1; KIT/CD117/c-Kit: KIT proto-oncogene receptor tyrosine kinase; HSCs: hematopoietic stem cells; HSPCs: hematopoietic stem and progenitor cells; Kyn: kynurenine; LSK: lineage- (Lin-), LY6A/Sca-1+, KIT/c-Kit/CD117+; LY6A/Sca-1: lymphocyte antigen 6 family member A; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; MTORC2: MTOR complex 2; OPP: O-propargyl-puromycin; PI3K: phosphoinositide 3-kinase; poly(I:C): polyinosinic:polycytidylic acid; RPS6/S6: ribosomal protein S6; tam: tamoxifen; TCA: tricarboxylic acid; TFEB: transcription factor EB; PTPRC/CD45: Protein Tyrosine Phosphatase Receptor Type C, CD45 antigen.
期刊介绍:
Autophagy is a peer-reviewed journal that publishes research on autophagic processes, including the lysosome/vacuole dependent degradation of intracellular material. It aims to be the premier journal in the field and covers various connections between autophagy and human health and disease, such as cancer, neurodegeneration, aging, diabetes, myopathies, and heart disease. Autophagy is interested in all experimental systems, from yeast to human. Suggestions for specialized topics are welcome.
The journal accepts the following types of articles: Original research, Reviews, Technical papers, Brief Reports, Addenda, Letters to the Editor, Commentaries and Views, and Articles on science and art.
Autophagy is abstracted/indexed in Adis International Ltd (Reactions Weekly), EBSCOhost (Biological Abstracts), Elsevier BV (EMBASE and Scopus), PubMed, Biological Abstracts, Science Citation Index Expanded, Web of Science, and MEDLINE.