Ttc7a regulates hematopoietic stem cell functions while controlling the stress-induced response

Area of Science:

• Hematology
• Stem Cell Biology
• Molecular Biology

Background:

• The intricate molecular mechanisms governing hematopoietic stem cell (HSC) self-renewal and differentiation remain incompletely understood.
• Identifying key regulators is crucial for understanding HSC function and potential therapeutic interventions.

Purpose of the Study:

• To investigate the role of tetratricopeptide repeat domain 7 A (Ttc7a) in regulating murine HSC behavior.
• To elucidate the functional impact of Ttc7a deficiency on HSC stemness and stress response.

Main Methods:

• In vivo competitive repopulating assays and serial cell transplantations were performed using Ttc7a-deficient and wildtype murine HSC.
• Transcriptomic profiling of Ttc7a-deficient HSC was conducted to identify altered gene expression patterns.
• In vitro and in vivo stress assays were employed to assess HSC proliferation under various stress conditions.

Main Results:

• Loss of Ttc7a significantly enhanced the competitive repopulating ability and self-renewal potential of HSC.
• Ttc7a-deficient HSC displayed altered transcriptomic profiles, particularly in genes related to cellular stress response.
• These HSC exhibited increased proliferation in response to both chemical and myeloablative stress.

Conclusions:

• Ttc7a acts as a critical intrinsic regulator of HSC stemness, controlling their proliferative capacity.
• The function of Ttc7a in HSC stemness is, in part, mediated through the regulation of the endoplasmic reticulum stress response.
• These findings uncover a novel role for Ttc7a in maintaining HSC homeostasis and response to stress.