1. p38α plays differential roles in hematopoietic stem cell activity dependent on aging contexts
- Author
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Daiki Karigane, Kinya Otsu, Shinichiro Okamoto, Nobuhito Goda, Takayuki Morikawa, Hiroshi Kobayashi, Yuriko Sorimachi, Yoshiaki Kubota, Yukako Ootomo, and Keiyo Takubo
- Subjects
0301 basic medicine ,Male ,Aging ,53BP1, tumor suppressor p53-binding protein 1 ,p38MAPK, p38 mitogen-activated kinase ,Ataxia Telangiectasia Mutated Proteins ,LSK, lineage−Sca-1+c-Kit+ cell ,MEXT, Ministry of Education, Culture, Sports, Science and Technology ,Biochemistry ,Atm, ataxia–telangiectasia mutated ,Mitogen-Activated Protein Kinase 14 ,Mice ,GSEA, gene set enrichment analysis ,Cellular Senescence ,Mice, Knockout ,Hematopoietic stem cell ,hemic and immune systems ,Cell Differentiation ,p38αfl/fl, p38αflox/flox ,Cell biology ,TNFα, tumor necrosis factor α ,Haematopoiesis ,medicine.anatomical_structure ,Phenotype ,p38MAPK ,Female ,Stem cell ,TAM, tamoxifen ,Research Article ,Premature aging ,Context (language use) ,pp38MAPK, phospholyrated-p38MAPK ,Biology ,PB, peripheral blood ,γH2AX, phosphorylated H2A histone family member X ,03 medical and health sciences ,ROS, reactive oxygen species ,HSC, hematopoietic stem cell ,Genetic model ,medicine ,Animals ,MPP, multipotent progenitor cell ,Molecular Biology ,BMMNCs, bone marrow–derived mononuclear cells ,Cell Proliferation ,030102 biochemistry & molecular biology ,Cell Biology ,LT-HSC, long-term HSC ,ataxia–telangiectasia ,Hematopoietic Stem Cells ,hematopoiesis ,BMT, bone marrow transplantation ,Transplantation ,Mice, Inbred C57BL ,030104 developmental biology ,CAG, chicken β-actin promoter with cytomegalovirus enhancer ,JSPS, Japan Society for the Promotion of Science ,Atmfl/fl, Atmflox/flox ,HSPC, hematopoietic stem/progenitor cell ,BM, bone marrow ,Bone marrow ,qPCR, quantitative PCR ,Reactive Oxygen Species ,transplantation - Abstract
Hematopoietic stem cells (HSCs) and their progeny sustain lifetime hematopoiesis. Aging alters HSC function, number, and composition and increases risk of hematological malignancies, but how these changes occur in HSCs remains unclear. Signaling via p38 mitogen-activated kinase (p38MAPK) has been proposed as a candidate mechanism underlying induction of HSC aging. Here, using genetic models of both chronological and premature aging, we describe a multimodal role for p38α, the major p38MAPK isozyme in hematopoiesis, in HSC aging. We report that p38α regulates differentiation bias and sustains transplantation capacity of HSCs in the early phase of chronological aging. However, p38α decreased HSC transplantation capacity in the late progression phase of chronological aging. Furthermore, codeletion of p38α in mice deficient in ataxia–telangiectasia mutated, a model of premature aging, exacerbated aging-related HSC phenotypes seen in ataxia–telangiectasia mutated single-mutant mice. Overall, these studies provide new insight into multiple functions of p38MAPK, which both promotes and suppresses HSC aging context dependently.
- Published
- 2021