Lin28 enhances tissue repair by reprogramming cellular metabolism

Area of Science:

• Developmental Biology
• Regenerative Medicine
• Molecular Biology

Background:

• Tissue regeneration capacity diminishes with age, with underlying mechanisms for enhanced juvenile repair remaining unclear.
• Lin28a, an RNA-binding protein crucial for embryogenesis, influences development, pluripotency, and metabolism.
• Investigating Lin28a's role in adult tissue repair could reveal novel regenerative strategies.

Purpose of the Study:

• To determine if Lin28a reactivation can enhance tissue repair in adult organisms.
• To elucidate the molecular mechanisms by which Lin28a influences tissue regeneration.
• To explore the potential of targeting Lin28a for therapeutic applications in regenerative medicine.

Main Methods:

• Engineered reactivation of Lin28a expression in adult models of tissue injury (hair follicles, cartilage, bone, mesenchyme).
• Assessed hair regrowth, cartilage, bone, and mesenchyme regeneration.
• Investigated the role of let-7 microRNA repression and cellular bioenergetics (glycolysis and oxidative phosphorylation) in Lin28a-mediated repair.

Main Results:

• Lin28a reactivation significantly improved hair regrowth and accelerated the repair of cartilage, bone, and mesenchyme.
• Lin28a's enhancement of repair required let-7 microRNA repression but was not solely dependent on it.
• Lin28a increased glycolysis and oxidative phosphorylation (OxPhos) by enhancing the translation of metabolic enzyme mRNAs.
• Inhibition of OxPhos negated Lin28a's pro-regenerative effects, while pharmacologically increasing OxPhos promoted repair.

Conclusions:

• Lin28a enhances tissue repair in specific adult tissues by reprogramming cellular bioenergetics.
• The study highlights the critical role of metabolic pathways, particularly OxPhos, in mediating Lin28a's regenerative effects.
• Targeting Lin28a and cellular metabolism presents a potential therapeutic avenue for improving tissue repair in aging populations.