TY - JOUR
T1 - p38α plays differential roles in hematopoietic stem cell activity dependent on aging contexts
AU - Sorimachi, Yuriko
AU - Karigane, Daiki
AU - Ootomo, Yukako
AU - Kobayashi, Hiroshi
AU - Morikawa, Takayuki
AU - Otsu, Kinya
AU - Kubota, Yoshiaki
AU - Okamoto, Shinichiro
AU - Goda, Nobuhito
AU - Takubo, Keiyo
N1 - Funding Information:
Funding and additional information—D. K. was supported in part by a KAKENHI grant from Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Society for the Promotion of Science (JSPS) (19K17877), JB research grants, and the Takeda Science Foundation. H. K. was supported in part by a KAKENHI grant from MEXT/JSPS (19K17847) and a grant from the National Center for Global Health and Medicine. K. T. was supported in part by KAKENHI grants from MEXT/JSPS (18H02845, 18K19570, and 20K21621), grants from the National Center for Global Health and Medicine (26-001 and 19A2002), a grant from Japan Health Research Promotion Bureau, Japan Agency for Medical Research and Development grants (JP18ck0106444, JP18ae0201014, JP20bm0704042, and JP20gm1210011), and grants from the Ono Medical Research Foundation, the Kanzawa Medical Research Foundation, and the Takeda Science Foundation.
Publisher Copyright:
© 2021 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jbc.2021.100563
DO - 10.1016/j.jbc.2021.100563
M3 - Article
C2 - 33745970
AN - SCOPUS:85104627546
SN - 0021-9258
VL - 296
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
M1 - 100563
ER -