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.
Highlights
Hematopoietic stem cells (HSCs) and their progeny sustain lifetime hematopoiesis
Several stress signals, including p38 mitogen-activated kinase (p38MAPK) signaling, reportedly function in HSC aging. p38MAPK is a member of the MAPK superfamily and includes four isozymes: the major isozyme p38α (Mapk14), p38β (Mapk11), p38γ (Mapk12), and p38δ (Mapk13). p38MAPK is activated by DNA damage, reactive oxygen species (ROS), and cytokine release, all induced by stress responses [9, 10]
We evaluated the number of longterm HSC (LT-HSC) in the bone marrow (BM), along with expression of
Summary
We investigated onset of HSC aging in WT mice to select time points appropriate for analysis of HSC aging in p38αΔ/Δ mice. After secondary BMT, p38αΔ/Δ mice showed comparable differentiation status in PB but higher relative PB chimerism than did the control p38α+/+ cell–transplanted group P38αΔ/Δ cell–transplanted groups showed higher BM chimerism of multipotent progenitor cells (MPPs) and a greater degree of differentiation in secondary recipients (Fig. 2I), supporting the idea that p38α deletion improves overall repopulation capacity after transplantation in the later phase of aging. Expression levels of p16Ink4a and p19Arf, tumor suppressors that are reportedly activated in stressed HSCs [13], did not differ between p38α+/+ and p38αΔ/Δ HSCs at steady state or after secondary BMT (Fig. S2, L and M) These results suggest that p38MAPK activity decreases HSC repopulation capacity after transplantation in the late progression phase of chronological aging. A p38α+/+ or p38αfl/fl mice TAM i.p
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