Neutralization of excessive levels of active TGF-β1 reduces MSC recruitment and differentiation to mitigate...

Area of Science:

• Biomedical Engineering
• Tissue Engineering
• Regenerative Medicine

Background:

• Peritendinous adhesion formation (PAF) restricts digital range of motion.
• The cellular origins of myofibroblasts in PAF remain incompletely understood.

Purpose of the Study:

• To elucidate the cellular mechanisms and signaling pathways driving peritendinous adhesion formation.
• To identify the origin of myofibroblasts in PAF and explore potential therapeutic targets.

Main Methods:

• Quantification of active TGF-β1, macrophages, mesenchymal stromal cells (MSCs), and myofibroblasts in human and mouse adhesion tissues.
• Genetic manipulation: knockout of TGF-β1 in macrophages and TGF-β1R2 in MSCs.
• Pharmacological intervention: systemic injection of TGF-β-neutralizing antibody 1D11.
• Assessment of MSC infiltration, myofibroblast differentiation, and collagen deposition.

Main Results:

• Elevated levels of active TGF-β1, macrophages, MSCs, and myofibroblasts were observed in PAF tissues.
• Macrophage-specific TGF-β1 knockout or MSC-specific TGF-β1R2 knockout significantly inhibited PAF.
• MSCs were identified as precursors to myofibroblasts in adhesion formation.
• TGF-β neutralization reduced MSC and myofibroblast infiltration, thereby limiting PAF.

Conclusions:

• Macrophage-derived TGF-β1 plays a critical role in recruiting MSCs, which then differentiate into myofibroblasts, driving PAF.
• Targeting the TGF-β1 signaling pathway presents a promising therapeutic strategy for mitigating peritendinous adhesions.