External signals regulate continuous transcriptional states in hematopoietic stem cells

Area of Science:

• Hematology
• Stem Cell Biology
• Immunology

Background:

• Hematopoietic stem cells (HSCs) are crucial for maintaining blood cell production under stress.
• In vivo heterogeneity and specificity of HSC responses to external stimuli remain incompletely understood.

Purpose of the Study:

• To investigate the in vivo heterogeneity and dynamic responses of mouse HSCs and LSK progenitors to pharmacological perturbations of niche signals.
• To identify HSC states and characterize their transcriptional and chromatin features in response to external stressors.

Main Methods:

• Single-cell RNA sequencing (scRNA-Seq) of functionally validated mouse HSCs and LSK progenitors.
• In vivo pharmacological perturbation using interferon, G-CSF, and prostaglandin.
• Single-cell ATAC sequencing (scATAC-Seq) for chromatin analysis.

Main Results:

• Identified six distinct HSC states with enriched marker gene expression.
• Observed rapid HSC state transitions and variable transcriptional responses to external signals.
• HSCs showed a stronger link between baseline and stress-induced molecular signatures compared to LSK progenitors.
• Discovered HSC-specific predispositions to niche signals via chromatin analysis.

Conclusions:

• External signals rapidly alter HSC states, with responses varying within the HSC population.
• HSCs possess intrinsic predispositions to niche signals, influencing their response to stress.
• Generated a resource of HSC and LSK progenitor features critical for understanding stress hematopoiesis and regenerative potential.