Human haematopoietic stem cells remember inflammatory stress.

Area of Science:

• Hematology
• Immunology
• Cell Biology
• Aging Research

Background:

• Inflammation is linked to aging and cancer, impacting blood cells.
• Human hematopoietic stem cells (HSCs) are crucial for lifelong blood production but their response to inflammation is poorly understood.
• Understanding HSC adaptation to inflammatory stress is vital for regenerative medicine and disease research.

Purpose of the Study:

• To investigate how human HSCs respond and adapt to inflammatory stress.
• To identify distinct HSC subsets based on their response to inflammation.
• To explore the physiological relevance and clinical implications of identified HSC subsets.

Main Methods:

• Development of xenograft inflammation-recovery models.
• Single-cell multiomics analysis of xenografted human HSCs.
• Analysis of HSC-iM program enrichment in various clinical conditions and population cohorts.

Main Results:

• Identification of two distinct HSC subsets, including HSC inflammatory memory (HSC-iM), which retains molecular memory of inflammation.
• HSC-iM exhibits quiescence and reduced hematopoietic output, with its program found in diverse conditions like COVID-19 recovery, sickle cell disease, aging, and clonal hematopoiesis.
• Clonal hematopoiesis mutations modulated inflammatory stress effects in HSC-iM, and the HSC-iM program was transmitted to immune progeny.
• Enrichment of the HSC-iM program in circulating blood cells correlated with increased all-cause mortality risk.

Conclusions:

• A novel HSC subset, HSC-iM, characterized by inflammatory memory, has been identified.
• The HSC-iM subset plays a role in modulating the response to inflammatory stress and has implications across various diseases and aging.
• HSC-iM represents a potential biomarker for health outcomes and mortality risk.