JMJD6 promotes self-renewal and regenerative capacity of hematopoietic stem cells
| Autor: | Jozef Durko, Andrea Tavosanis, Peter Giles, Hannah Lawson, Alena Shmakova, Nicholas M. Morton, Douglas Vernimmen, Dónal O'Carroll, Marie O'Shea, Neil P. Rodrigues, Amelie V. Guitart, Melania Barile, Andreas Lengeling, Kamil R. Kranc, Roderick N. Carter, Berthold Göttgens, Elise Georges, Milica Vukovic, Lewis Allen, Penny Timms, Catarina Sepulveda, Christopher J. Schofield, Joana Campos, Louie N. van de Lagemaat |
|---|---|
| Přispěvatelé: | Gottgens, Berthold [0000-0001-6302-5705], Apollo - University of Cambridge Repository |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Hematopoiesis and Stem Cells Cell Differentiation Hematology mTORC1 Biology Hematopoietic Stem Cells Cell biology Hematopoiesis Transplantation 03 medical and health sciences Haematopoiesis 030104 developmental biology 0302 clinical medicine Alpha ketoglutarate medicine.anatomical_structure Bone Marrow 030220 oncology & carcinogenesis medicine Lymphoid Progenitor Cells Bone marrow Progenitor cell Stem cell Bone Marrow Transplantation |
| Zdroj: | Blood Adv Lawson, H, Sepulveda, C, van de Lagemaat, L N, Durko, J, Barile, M, Tavosanis, A, Georges, E, Shmakova, A, Timms, P, Carter, R N, Allen, L, Campos, J, Vukovic, M, Guitart, A V, Giles, P, O'Shea, M, Vernimmen, D, Morton, N M, Rodrigues, N P, Göttgens, B, Schofield, C J, Lengeling, A, O'Carroll, D & Kranc, K R 2021, ' JMJD6 promotes self-renewal and regenerative capacity of hematopoietic stem cells ', Blood Advances, vol. 5, no. 3, pp. 889-899 . https://doi.org/10.1182/bloodadvances.2020002702 |
| ISSN: | 2473-9529 |
| DOI: | 10.17863/cam.61889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|