دورية أكاديمية
JMJD6 promotes self-renewal and regenerative capacity of hematopoietic stem cells.
| العنوان: | JMJD6 promotes self-renewal and regenerative capacity of hematopoietic stem cells. |
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| المؤلفون: | Lawson H; Laboratory of Haematopoietic Stem Cell and Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom., Sepulveda C; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom., van de Lagemaat LN; Laboratory of Haematopoietic Stem Cell and Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom., Durko J; Laboratory of Haematopoietic Stem Cell and Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom., Barile M; Department of Haematology, Wellcome and Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom., Tavosanis A; Laboratory of Haematopoietic Stem Cell and Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom., Georges E; Laboratory of Haematopoietic Stem Cell and Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom., Shmakova A; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom., Timms P; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom., Carter RN; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom., Allen L; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom., Campos J; Laboratory of Haematopoietic Stem Cell and Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom., Vukovic M; Laboratory of Haematopoietic Stem Cell and Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom., Guitart AV; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom., Giles P; Wales Gene Park and Wales Cancer Research Centre, Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom., O'Shea M; Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom., Vernimmen D; Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom., Morton NM; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom., Rodrigues NP; European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom., Göttgens B; Department of Haematology, Wellcome and Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom., Schofield CJ; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom., Lengeling A; Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.; Administrative Headquarters, Max Planck Society, Munich, Germany; and., O'Carroll D; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.; Institute for Stem Cell Research and.; Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom., Kranc KR; Laboratory of Haematopoietic Stem Cell and Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom. |
| المصدر: | Blood advances [Blood Adv] 2021 Feb 09; Vol. 5 (3), pp. 889-899. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society of Hematology Country of Publication: United States NLM ID: 101698425 Publication Model: Print Cited Medium: Internet ISSN: 2473-9537 (Electronic) Linking ISSN: 24739529 NLM ISO Abbreviation: Blood Adv Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : American Society of Hematology, [2016]- |
| مواضيع طبية MeSH: | Hematopoiesis* , Hematopoietic Stem Cells*, Bone Marrow ; Bone Marrow Transplantation ; Cell Differentiation |
| مستخلص: | Lifelong multilineage hematopoiesis critically depends on rare hematopoietic stem cells (HSCs) that reside in the hypoxic bone marrow microenvironment. Although the role of the canonical oxygen sensor hypoxia-inducible factor prolyl hydroxylase has been investigated extensively in hematopoiesis, the functional significance of other members of the 2-oxoglutarate (2-OG)-dependent protein hydroxylase family of enzymes remains poorly defined in HSC biology and multilineage hematopoiesis. Here, by using hematopoietic-specific conditional gene deletion, we reveal that the 2-OG-dependent protein hydroxylase JMJD6 is essential for short- and long-term maintenance of the HSC pool and multilineage hematopoiesis. Additionally, upon hematopoietic injury, Jmjd6-deficient HSCs display a striking failure to expand and regenerate the hematopoietic system. Moreover, HSCs lacking Jmjd6 lose multilineage reconstitution potential and self-renewal capacity upon serial transplantation. At the molecular level, we found that JMJD6 functions to repress multiple processes whose downregulation is essential for HSC integrity, including mitochondrial oxidative phosphorylation (OXPHOS), protein synthesis, p53 stabilization, cell cycle checkpoint progression, and mTORC1 signaling. Indeed, Jmjd6-deficient primitive hematopoietic cells display elevated basal and maximal mitochondrial respiration rates and increased reactive oxygen species (ROS), prerequisites for HSC failure. Notably, an antioxidant, N-acetyl-l-cysteine, rescued HSC and lymphoid progenitor cell depletion, indicating a causal impact of OXPHOS-mediated ROS generation upon Jmjd6 deletion. Thus, JMJD6 promotes HSC maintenance and multilineage differentiation potential by suppressing fundamental pathways whose activation is detrimental for HSC function. (© 2021 by The American Society of Hematology.) |
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| معلومات مُعتمدة: | MC_PC_17230 United Kingdom MRC_ Medical Research Council; MR/P010008/2 United Kingdom MRC_ Medical Research Council; United Kingdom BB_ Biotechnology and Biological Sciences Research Council; 26787 United Kingdom CRUK_ Cancer Research UK; MR/K017047/1 United Kingdom MRC_ Medical Research Council; MR/P010008/1 United Kingdom MRC_ Medical Research Council; 14633 United Kingdom CRUK_ Cancer Research UK; United Kingdom WT_ Wellcome Trust |
| تواريخ الأحداث: | Date Created: 20210209 Date Completed: 20210528 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| مُعرف محوري في PubMed: | PMC7876897 |
| DOI: | 10.1182/bloodadvances.2020002702 |
| PMID: | 33560400 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 2473-9537 |
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| DOI: | 10.1182/bloodadvances.2020002702 |