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

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.