p38α plays differential roles in hematopoietic stem cell activity dependent on aging contexts

J Biol Chem. Jan-Jun 2021;296:100563. doi: 10.1016/j.jbc.2021.100563. Epub 2021 Mar 18.

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.

Keywords: aging; ataxia–telangiectasia; hematopoiesis; hematopoietic stem cells; p38MAPK; transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Aging / pathology*
  • Animals
  • Ataxia Telangiectasia Mutated Proteins / physiology
  • Cell Differentiation*
  • Cell Proliferation
  • Cellular Senescence*
  • Female
  • Hematopoiesis
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 14 / physiology*
  • Phenotype
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Mitogen-Activated Protein Kinase 14