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

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 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 (from young to 1-year-old). However, p38α decreased HSC transplantation capacity in the late progression phase of chronological aging (from 1- to 2-years-old). Furthermore, co-deletion of p38α in mice deficient in Ataxia-telangiectasia mutated (Atm), a model of premature aging, exacerbated aging-related HSC phenotypes seen in Atm single mutant mice. Mechanistically, p38α makes a positive contribution to inflammation during the late phase aging, resulting in defects in 2-year-old HSCs. Overall, we propose multiple functions of p38MAPK, which both promotes and suppresses HSC aging context-dependently. we injected CAG-CreERT2: p38αflox/flox (p38αfl/fl) mice aged approximately 1 year (50–60 weeks) with TAM to delete p38α, and then analyzed those mice and corresponding controls 1 year later (i.e., at 2 years-of-age) (p38αcKO). lineage-Sca-1+c-Kit+CD34-Flt3- cells (LT-HSC) in the bone marrow (femur and tibia) from 2-year-old wild type (WT) or p38αcKO C57BL/6J mice (Ly5.2) were sorted into SF-O3 medium. Then, sorted cells were centrifuged at 340 x g for 5 min at 4°C and lysed with 75µL RLT buffer + 0.75µL 2-ME. RNA extraction, cDNA synthesis, microarray analysis, and data normalization were outsourced to DNA Chip Research Inc.