Absence of the primary cilia formation gene Talpid3 impairs muscle stem cell function

Area of Science:

• Cell Biology
• Developmental Biology
• Regenerative Medicine

Background:

• Skeletal muscle stem cells (MuSC) maintain tissue homeostasis and repair.
• Primary cilia are present in quiescent MuSC and disassemble upon activation.
• The role of primary cilia in in vivo muscle regeneration is not fully understood.

Purpose of the Study:

• To investigate the role of Talpid3 (TA³), essential for primary cilia formation, in MuSC self-renewal and muscle regeneration in vivo.
• To identify signaling pathways affected by TA³ depletion in MuSC.
• To explore therapeutic strategies for restoring muscle regeneration.

Main Methods:

• Tamoxifen-inducible conditional deletion of TA³ in MuSC (iSC-KO).
• Assessment of muscle regeneration following cytotoxic injury.
• Single-cell transcriptomics analysis of MuSC progeny.
• Pharmacological manipulation of Hedgehog (Hh) and Wnt signaling pathways.

Main Results:

• TA³ deletion in MuSC impairs muscle regeneration and MuSC self-renewal after injury.
• TA³ depletion leads to deregulation of Hh and Wnt signaling pathways.
• Pharmacological Wnt activation restores muscle regeneration, while Hh pathway activation shows no effect.

Conclusions:

• TA³ and primary cilia are essential for MuSC self-renewal and effective muscle regeneration.
• Wnt signaling pathway activation is a promising therapeutic approach to restore muscle repair.
• Targeting primary cilia function presents a potential strategy for regenerative medicine.