AMPKa1 Deficiency in Macrophages Impairs Tendon Regeneration and Tendon Stem Cell Function via TNF-a–FBP2 Signaling
Tendon healing is limited by the minimal intrinsic regenerative capacity of the tissue, resulting in the formation of fibrovascular scar tissue rather than functional regeneration. Macrophage immunometabolism governs the balance between inflammation and repair; however, its effects on tendon regeneration are poorly understood. In this study, we investigated the differential activation of macrophage AMP-activated protein kinase (AMPK) and its phenotypic alterations in neonatal and adult tendon injury models. Using myeloid-specific AMPKa1 knockout (LysM-Cre; Ampka1fl/fl) mice, we found that macrophage AMPKa1 deficiency impairs tendon regeneration and repair capacity, leading to compromised proliferation, migration, and differentiation functions of tendon stem/progenitor cells (TSPCs). Mechanistically, AMPKa1-deficient macrophages exhibited increased TNF-a production, which promoted the expression of Fructose-bisphosphatase 2 (FBP2) in a PI3K/AKT-dependent manner. In addition, knockdown of Fbp2 rescued mitochondrial dysfunction in TSPCs and facilitated tissue repair and regeneration. Collectively, these findings underscore the immunometabolism mechanism linking macrophage AMPKa1 activity to stem cell injury responses via a TNF-a–FBP2 axis and provide potential therapeutic targets for regulating stem cells. Overall design: tendon tissues from control and Lysm-Cre; Ampka1fl/fl mice (3 mice per condition, neonatal mice) were snap frozen in liquid nitrogen for further analyses.