MYCT1 controls environmental sensing in human haematopoietic stem cells

Area of Science:

• Hematology
• Stem Cell Biology
• Molecular Biology

Background:

• Human hematopoietic stem cell (HSC) self-renewal and engraftment are poorly understood and difficult to replicate in culture.
• Current methods struggle to reliably expand functional HSCs for therapeutic applications.

Purpose of the Study:

• To identify key regulators of human HSC self-renewal and engraftment.
• To investigate the role of MYC target 1 (MYCT1) in maintaining HSC stemness during culture.

Main Methods:

• Lentivirus-mediated knockdown and overexpression of MYCT1 in human fetal liver and cord blood (CB) hematopoietic stem and progenitor cells (HSPCs).
• Single-cell RNA sequencing to analyze gene expression changes.
• Assays to assess HSPC expansion, engraftment, endocytosis rates, and mitochondrial activity.

Main Results:

• MYCT1 is selectively expressed in undifferentiated HSPCs and downregulated during culture.
• MYCT1 knockdown impaired HSPC expansion and engraftment.
• Restoring MYCT1 expression enhanced expansion and engraftment of cultured CB HSPCs.
• MYCT1 regulates ETS factor expression, mitochondrial activity, and endocytosis, preserving HSC stemness.

Conclusions:

• MYCT1 is a crucial regulator of human HSC stemness, moderating endocytosis and environmental sensing.
• MYCT1 downregulation during culture is a vulnerability that compromises HSC expansion.
• Targeting MYCT1 offers a potential strategy to improve HSC expansion and therapeutic applications.