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Psychological stress drives aging-like hematopoietic stem cell dysfunction through a brain-gut-bone marrow axis

Xiaobin Tian1, Binghuo Wu2, Keyue Yang3

  • 1RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.

Cell Stem Cell
|July 2, 2026
PubMed

Insights

Psychological stress impairs hematopoietic stem cell (HSC) function, causing aging-like changes. This occurs via a brain-gut-bone marrow axis involving reduced spermidine and altered gut bacteria, impacting HSC self-renewal and differentiation.

Area of Science:

  • Neuroscience
  • Immunology
  • Microbiology
  • Gerontology

Background:

  • Chronic stress impacts hematopoietic stem cells (HSCs), but the regulatory mechanisms are unclear.
  • Psychological stress is known to affect various physiological systems, including the immune system and stem cell function.

Purpose of the Study:

  • To elucidate the mechanisms by which psychological stress regulates HSC function.
  • To identify the specific brain regions, microbial factors, and metabolic pathways involved in stress-induced HSC dysfunction.

Main Methods:

  • Investigated the effects of psychological stress on HSC self-renewal and lymphoid differentiation in vivo.
  • Utilized chemogenetics to manipulate neuronal activity in the medial prefrontal cortex (mPFC) and periaqueductal gray (PAG).
  • Analyzed gut microbiota composition (L. reuteri), spermidine levels, mitochondrial autophagy, and oxidative/ferroptotic stress in HSCs.

Main Results:

  • Psychological stress impairs HSC self-renewal and lymphoid differentiation, inducing aging-like phenotypes.
  • Stress suppresses mPFC and PAG neuronal activity, leading to HSC dysfunction; activation of these regions restores HSC function.
  • Stress reduces L. reuteri abundance and spermidine levels, which suppresses mitochondrial autophagy and promotes oxidative and ferroptotic stress in HSCs.
  • A sympathetic pathway links mPFC/PAG activity to reduced intestinal mucin, L. reuteri, and spermidine.

Conclusions:

  • Psychological stress induces aging-like HSC dysfunction through a brain-gut-bone marrow axis.
  • The sympathetic nervous system mediates stress effects on the gut microbiota and spermidine metabolism, impacting HSCs.
  • Targeting this axis may offer therapeutic strategies for stress-related HSC dysfunction and aging.

Keywords:
agingautophagyhematopoietic stem cellintestinal environmentlymphoid differentiationmetabolismmicrobiotapsychological stressspermidinesympathetic pathway

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