TWIST1 preserves hematopoietic stem cell function via the CACNA1B/Ca2+/mitochondria axis

Area of Science:

• Hematology
• Stem Cell Biology
• Mitochondrial Biology

Background:

• Hematopoietic stem cells (HSCs) are crucial for blood cell formation and survival.
• Mitochondrial function significantly impacts HSC fate and maintenance.
• Mechanisms controlling HSC regulation, particularly mitochondrial roles, are not fully understood.

Purpose of the Study:

• To identify novel regulators of HSC maintenance.
• To investigate the role of transcription factor TWIST1 in HSC function.
• To elucidate the mechanisms by which TWIST1 modulates mitochondrial function in HSCs.

Main Methods:

• Genetic deletion of Twist1 in HSCs.
• Analysis of HSC frequency, dormancy, self-renewal, and differentiation.
• Assessment of HSC response to genotoxic stress (irradiation, 5-fluorouracil).
• Investigation of mitochondrial calcium levels, metabolic activity, and ROS production.
• Pharmacological inhibition of voltage-gated calcium channels (VGCCs).

Main Results:

• Twist1 deletion decreased lymphoid-biased HSCs, dormancy, and self-renewal, skewing differentiation towards myeloid lineages.
• Twist1-deficient HSCs showed reduced stress tolerance and senescence phenotypes.
• Mechanistically, Twist1 deletion upregulated Cacna1b (VGCC), increasing mitochondrial calcium, metabolic activity, and ROS.
• Calcium channel blockade rescued TWIST1-deficient HSC defects under normal and stress conditions.

Conclusions:

• TWIST1 is a critical regulator of HSC maintenance and function.
• TWIST1 acts via the CACNA1B/Ca2+/mitochondria axis to control HSC fate.
• Calcium signaling is essential for HSC maintenance and response to stress.