Hematopoietic stem cell regulation by p38MAPK in aging

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17877
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Karigane Daiki 国立研究開発法人国立国際医療研究センター, その他部局等, 客員研究員 (60594588)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 造血幹細胞 / 老化 / p38MAPK / ATM

Outline of Final Research Achievements

Hematopoietic stem cells (HSCs) 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. Using genetic models of both chronological and premature aging, we describe a multimodal role for p38a in HSC aging. We report that p38a regulates differentiation bias and sustains the transplantation capacity of HSCs in the early phase of chronological aging. However, p38a decreased HSC transplantation capacity in the late progression phase of chronological aging. Furthermore, co-deletion of p38a in mice deficient in Atm, a model of premature aging, exacerbated aging-related HSC phenotypes seen in Atm single mutant mice. Overall, these studies provide new insight into multiple functions of p38MAPK, which both promote and suppress HSC aging context-dependently.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

現在は高齢化社会であり、血液疾患のみならず、多くの疾患は老化が大きな要因となって発症します。しかし老化とは何か、老化がどのように疾患の進展に影響するかなどは、まだ不明な部分が多く残っています。我々は老化を代表的な慢性ストレスととらえ、生理学的老化および早老症モデルにおける造血幹細胞の機能を解析し、上記問題の解明を試みました。結果、老化は一様ではなく、早期・後期で異なる分子機構が寄与している可能性が示唆されました。また早老症モデルは必ずしも生理学的老化とは同じではなく、異なる機構が存在すると考えられました。